Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists

Abstract

Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing –S– → –CH₂– replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure–activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1.

Graphical Abstract

1. Introduction

Opioid overdose deaths are a major public health concern with rates continuing to rise. The opioid crisis is a complex problem with challenging socioeconomic elements driven by the fact that morphine and its analogues are essential pain-alleviating agents whose use is accompanied by dependence and respiratory depression.[1–3] The action of classical opioids is mediated via the G protein coupled mu-, delta-, and kappa-opioid receptors, with the mu receptor being the primary target of addictive opioids, such as heroin and fentanyl.[4, 5] In contrast, drugs that selectively target the kappa opioid receptor (KOR) represent an attractive alternative because they are antinociceptive agents,[6–9] but do not produce reward seeking behavior.[10–12] KOR agonists have also been of interest for the treatment of pruritis.[13–15] However, classical KOR agonists are known to produce dysphoria and sedation, which has limited their further therapeutic development. [7, 9, 16–18] It has been hypothesized that G protein signaling-biased agonists can untangle the desired analgesic and anti-pruritic effects of KOR agonists from the undesired side effects.[9, 19–22]

Despite the liabilities associated with KOR activation, numerous small molecule KOR agonists have been reported, including U69,593,[23] ketazocine,[24, 25] 6′-guanidinonaltrindole,[26–28] HS665,[29, 30] salvinorin A[31], and the salvinorin A derivative RB-64[32] (Figure 1). In 2009, Japan approved the first KOR agonist, nalfurafine, for the treatment of hemodialysis-induced pruritus.[33] Nalfurafine has been reported to be biased towards ERK1/2 activation over its ability to activate p38α.[34] However, nalfurafine has yet to be approved for clinical use outside Japan and South Korea.[35] Robust research efforts also continue the search for KOR-selective peptide agonists (recent review[36]). One notable example is difelikephalin, which has been approved for the treatment of pruritis.[37]

Figure 1.

Structures of representative KOR agonists.

In 2012 we identified four novel KOR agonist chemotypes via high-throughput screening, including one triazole scaffold.[38] Further development led to the identification of triazole 1.1 (1) which is a potent, G protein-biased KOR agonist (Figure 2).[39] Studies in mice show that triazole 1.1 has antinociceptive and anti-pruritic properties comparable to the classic KOR agonist U50,488H, while avoiding sedative effects traditionally associated with KOR agonists.[9] This work verified that the anti-pruritic and antinociceptive effects of triazole 1.1 arose from selective action at KORs; however, unlike that observed for U50,488H, dopamine levels were not decreased in the nucleus accumbens upon triazole 1.1 treatment.[9] Analogous anti-pruritic and non-sedative properties have been reported for non-human primates[16, 40] and triazole 1.1 has been found to reduce oxycodone self-administration in male rhesus monkeys.[41]

Figure 2.

Structure of triazole 1.1 and proposed replacement of the sulfur-containing side chain with carbon-linked side chains at C5 in the new series (note the priority change in heterocycles numbering when changing from sulfur to carbon).

Our initial structure-activity relationship (SAR) studies on triazole 1.1 focused on the three arms of the triazole,[42, 43] but we did not vary the sulfur-containing linker at C-3 in that work. In this study, we report an adjacent series of triazole-based KOR agonists in which the sulfur containing side chain is replaced with a carbon side chain (Figure 2). A similar approach has also been used to explore triazole SAR in other contexts with various outcomes.[44–48] Additionally, we looked to map out the chemical space about the appendages (Ar₁, Ar₂, and Ar₃) for this new series. Specific attention was focused on improving potency and G protein bias compared to triazole 1.1 as well as a secondary goal of investigating the relationship between the scaffold and microsomal stability. This approach led to the discovery of a single-digit nM agonist at the G protein signaling pathway (4j) and analogues with bias factors greater than 70 (4d, 4i and 4j), affording new probes for the pharmacological investigation of G protein-biased KOR agonists.

2. Results and Discussion

2.1. Structure-Activity Relationship Studies.

Pharmacological activity was assessed using cell lines expressing the human KOR. For G protein signaling, we determined ³⁵S-GTPγS binding in membranes. To assess βarrestin2 recruitment to KOR, an enzyme fragment complementation assay (DiscoverX PathHunter^®) was used as previously described.[39] Concentration response curves were analyzed by nonlinear regression analyses and application of the operational model for biased agonism was applied (see methods); bias factors are presented in the tables.

We first investigated the effect of chain length on the aryl-containing C-5 substituent by designing analogues in which the three appendages were consistent with triazole 1.1, but the carbon chain length between the triazole core and the C-5 substituent was varied. The GTPγS binding potency steeply depended on the number of carbons, with compound 2b, containing a 2-carbon linker, being optimal (Table 1). The observation that direct –S– to –CH₂– modification affords an agonist of similar potency to triazole 1.1 (21 nM for 2b vs. 31 nM for triazole 1.1) indicates that sulfur is not essential for KOR agonism.

Table 1.

Structure-Activity Relationship Investigation of Linker Length on KOR Activity

		GTPySa				Parrestin2b
comp	n	EC50 (nM)	95% CI	Emax (%U69)	95% CI	EC50 (nM)	95% CI	Emax (%U69)	95% CI	bias
U69,593		43	38–49	100	–	55	50–61	100	–	1
2a	1	nc	–	–	–	nc	–	–	–	–
2b	2	21	14–32	90	85–95	803	489–1342	118	104–134	15
2c	3	807	483–1354	82	71–95	nc	–	–	–	–

^a35S-GTPγS binding assay of KOR G protein activation (n ≥ 3).

^bβarrcstin2 recruitment assay (n = 3 for 2b, 2c; 2 for 2a).

^cBias factor as calculated by published methods. [39] EC₅₀ and E_max are presented with 95% confidence intervals, nc is nonconvergent to regression analysis. For 2b, the analysis of bias factor is modified to account for E_max exceeding the reference agonist in the βarrcstin assay (see methods).

Similar to previous SAR studies on triazole 1.1,[38, 39, 42, 43] we explored the effect of variously substituted aromatic groups at the 4-N-position on KOR activation (Table 2). We were particularly interested in replacing the furan moiety with other heterocycles due to the metabolism concerns associated with this moiety. Both thiophene and thiazole replacements led to analogues of similar potency, with 2-thiophene being most potent at 11 nM (2d). Replacement of the furanylmethyl group with a benzyl substituent led to a slight decrease in potency (2f, 83 nM) but the direct attachment of a phenyl to N-4 led to the inactive 2g, showing the importance of the methylene linker for the positioning of the aromatic ring. Some pyridine rings were also tolerated, with 3-pyridyl (2i) being preferred but 2-pyridyl (2h) was less active and 4-pyridyl (2j) was inactive. Finally, due to the frequency of cyclopropane substituents in opioid agonists,[49] we tried a cyclopropane substitution, which decreased potency 10-fold (2k).

Table 2.

Structure-Activity Relationship Investigation of Effect of 4-N Substituent on KOR Activity

^a35S-GTPγS binding assay of KOR G protein activation (n ≥ 3).

^bβarrestin2 recruitment assay (n ≥ 3; for 2k, n = 1).

^cBias factor as calculated by published methods.[39] EC₅₀ and E_max are presented with 95% confidence intervals. nc is nonconvergent to analysis. For 2b, 2f, 2h, 2i and 2k, the analysis of bias factor is modified to account for E_max exceeding the reference agonist in the βarrestin assay (see methods).

Led by the modest increase in potency when the furan was replaced by a thiophene (2b vs 2d), the thiophene was held constant in the 4-N position while a survey of various aromatic heterocycles at the 3-position of the triazole was investigated. Only limited changes at this position were tolerated (Table 3). A 2-pyridyl nitrogen was required for activity. Removing this nitrogen (3a) or changing its location with respect to the triazole core (3b, 3c) resulted in significant loss of activity. Retaining this feature, we found that the additional nitrogen in pyrimidine (3d) led to a slight decrease in potency relative to 2d, but that potency was retained when the pyridine ring was 3-methyl-substituted (3f). In contrast, extension of this side chain to naphthyl and quinoline substitutions was not well tolerated (3g-3i), whereas a smaller N-methyl imidazole in the 2-position (3j) was fine.

Table 3.

Effect of Modifications of 3-Substitution on KOR Agonist Activity

^a35S-GTPγS binding assay of KOR G protein activation (n ≥ 3).

^bβarrestin2 recruitment assay (n ≥ 3; for 3e, n=2).

^cBias factor as calculated by published methods.[39] EC₅₀ and E_max are presented with 95% confidence intervals. nc is nonconvergent to analysis. For 3d, 3f, and 3j, the analysis of bias factor is modified to account for E_max exceeding the reference agonist in the βarrestin assay (see methods).

Finally, we investigated the effect of substitution on the phenyl group attached to the C-5 side chain (Table 4). Triazole 4a, bearing a simple 2-phenylethyl group at this position, was not potent (926 nM). Although electron-donating groups were tolerated (e.g., 4b), electron withdrawing groups were preferred. For mono substitution, placement of a para-bromo group was best (4e) and only a modest decrease noted for the corresponding meta isomer (4f), but a ca. 10-fold decrease for the ortho bromophenylethyl group (4g) was observed. Addition of a second electron withdrawing group (4j) resulted in an increase in potency to single digit nM. Placement of the second electron withdrawing group is consistent with those observed in the monosubstitution case in which the 3,4 isomer (4j) is more potent than the 2,4 isomer (4i) Interestingly, a 1-naphthylethyl group was not well tolerated (4k) but 2-napthyl substitution retained potency (4l). Importantly, the gain in G protein-signaling potency did not sacrifice G protein-signaling bias for several agonists.

Table 4.

Effect of Modifications at Ar3 on KOR Agonist Activity

^a35S-GTPγS binding assay of KOR G protein activation (n ≥ 3).

^bβarrestin2 recruitment assay (n ≥ 3; for 4g, n=2).

^cBias factor as calculated by published methods.[39] EC₅₀ and E_max are presented with 95% confidence intervals. nc is nonconvergent to analysis. For 4d, 4f, 4i and 4l, the analysis of bias factor is modified to account for E_max exceeding the reference agonist in the βarrestin assay (see methods).

Since replacement of the thioether side chain with a carbon side chain was the motivation behind this series, we examined the effects of unsaturation and substitution on the C-5 linker to the aryl group. The alteration between thiophene and furan in the series is a result of synthetic utility. In the case where Scheme 1 could be employed, thiophene was used in the 4-N position. However, in the case where Schemes 3 and 4 were used, furan was used in the 4-N position due to the ease of access of furfuryl isothiocyanate over 2-(isothiocyanatomethyl)thiophene. We first prepared one analogue in which rotation of the carbon side chain was restricted by incorporation of a cyclohexane ring, which was detrimental to activity (5a). Next, we designed several analogues in which the carbon side chain had varying degrees of unsaturation. In all cases, a dramatic loss in potency was observed (5b, 5c, 5d). All triazoles that were prepared containing added alcohols or ketones on the ethylene moiety were mostly inactive 5e (20%), 5f (4%), 5h (17%) (% GTPγS stimulation at 10 μM). While several attempts were made to access the β ketone analogue of compound 5h via oxidation, synthetic challenges precluded investigation of this analogue. Monofluorination at the α position (5g) resulted in a 3-fold loss of potency compared to compound 4a, while similar substitution at the β position (5i) retained the potency of the parent compound (4a). Unsurprisingly, complete removal of the carbon linker (5j) resulted in loss of activity.

Scheme 1. Representative Synthesis of 3,4,5-Trisubstituted 1,2,4-Triazoles^a.

^aReagents and conditions: (a) acid (1.0 equiv), DMAP (0.1 equiv), CDI (1.5 equiv), THF (0.2 M), 30 minutes, then amine (1.1 equiv), 3.5 h, rt; (b) amide (1.0 equiv), Lawesson’s reagent (1.2 equiv), toluene (0.1 M), 4 h, reflux; (c) acid (1.0 equiv), H₂SO₄ (0.1 equiv), MeOH (2 M), reflux, 2 h then H₂NNH₂, reflux, 3 h; (d) thioamide (1.0 equiv), hydrazide (1.2 equiv), AgOBz (2.0 equiv), HOAc (3.0 equiv), DCM (0.2 M), 15 h, rt; (e) thioamide (1.0 equiv), picolinohydrazide (1.2 equiv), AgOBz (2.0 equiv), HOAc (3.0 equiv), DCM (0.2 M), 15 h, rt; (f) thioamide (1.0 equiv), 1-methyl-1H-imidazole-2-carbohydrazide (1.2 equiv), AgOBz (2.0 equiv), HOAc (3.0 equiv), DCE (0.2 M), 60 °C, 2 days.

Scheme 3. Synthesis of 5b and 5c^a.

^aReagents and conditions: (a) picolinohydrazide (1.0 equiv), 2-(isothiocyanatomethyl)furan (1.0 equiv), ACN (0.2 M), 18 h, rt, 58%; (b) 12, 4 M NaOH, 2 h, rt, 85%; (c) 13 (1.0 equiv), HOAc (0.7 M), 30% H₂O₂ (2.2 equiv), DCM (0.5 M) 5h, 0 °C to rt, 52%; (d) 14 (1.0 equiv) paraformaldehyde (5 equiv), p-xylene (0.2 M), 4 h, reflux, 27%; (e) 15 (1.0 equiv) MnO₂ (10.5 equiv), THF (0.2 M), 4 h, rt, 57%; (f) 16 (1.0 equiv) Ohira-Bestmann reagent (1.3 equiv), K₂CO₃ (2.0 equiv), MeOH (0.2 M), 17.5 h, rt, 53%; (g) aryl iodide (1.0 equiv), 17 (2.0 equiv), CuI (0.12 equiv), PdCl₂(PPh₃)2 (0.06 equiv), TEA (0.2 M), 75°C, 19 h, 38%; (h) 5b (1.0 equiv), Lindlar’s catalyst (0.1 equiv), THF (0.2 M), rt, 3 h, 34%.

Scheme 4. Synthesis of 5e, 5f, and 5g^a.

^aReagents and Conditions: (a) benzylmagnesium chloride (1.0 equiv), THF (0.2 M), 1 h, rt, 68%; (b) 5e (1.0 equiv), MnO₂ (10.5 equiv), THF (0.2 M), 25 h, rt, 16%; (c) 5e (1.0 equiv), DAST (1.96 equiv), DCM (0.055 M), 16 h, −78 °C to rt, 57%;

We further explored a concise set of analogues where the C-5 group was held constant at (E)-(4-methyl-3-trifluoromethyl)phenylethenyl and the N-4 and C-3 groups were modified (Table 6). We were interested to see if modifications to the appendages could rescue the activity that was lost due to the introduction of a trans double bond in the carbon linker. Specifically, furan, thiophene and thiazole were used in the 4-N position as they proved to be active contributors in Table 2 and 2-pyridine and 1-methyl-1H-imiadzole were used in the Ar₁ position as they proved to be active contributors in Table 3. In all cases, there was a dramatic loss in potency of these analogues and activity was not rescued from appendage modifications.

Table 6.

Investigation of trans-Alkenes as KOR Agonists

^a35S-GTPγS binding assay of KOR G protein activation (n ≥ 3).

^bβarrestin2 recruitment assay (n ≥ 3).

^cBias factor as calculated by published methods.[39] nc is nonconvergent

2.2. Receptor selectivity and biased agonism.

Previously reported triazoles had high selectivity for engagement at the kappa receptor relative to the mu and delta opioid receptors (MOR and DOR, respective). Here, we determined the binding of 10 μM compound 2d to the KOR, MOR, and DOR by its ability to inhibit binding of an appropriate radiolabeled receptor ligand. Thus, while 2d completely inhibited U69,593 binding under these conditions (99.7% averaged over four experiments), binding of standard ligands to MOR and DOR was poorly inhibited under analogous conditions (30.9% and 30.7%, respectively). The Ki value for compound 2d was measured to be 5.8 nM; Ki values at the MOR and DOR were not determined.

Compounds that had measurable potencies in both G protein and βarrestin2 recruitment were analyzed for bias by nonlinear regression curve fitting to the operational model using U69,593 as a within assay reference agonist.[39] In general, bias can be observed when a compound performs better than U69,593 in one assay and worse than U69,593 in the other. In some cases, where agonist potency is poor, the bias estimate may represent a lower bound of the confidence window and the actual bias may be understated. Moreover, in cases where the efficacy in the βarrestin recruitment assay exceeded the maximum of the reference agonist, U69,593, constraints to the model were applied to approximate bias (see methods) [39]. Importantly, all of the potencies were determined in parallel with U69,593 assayed on the same plate.

As previously discussed, various 5 and 6-membered heterocycles were tolerated in the Ar₂ position in terms of GTPγS potency (Table 2). Similarly, both 5 and 6-membered heterocycles were tolerated in terms of G protein bias. Due to the necessity of a nitrogen in the 2-position of Ar₁ for G protein potency, elucidation of the relationship between this substituent and bias was hampered. A variety of substituents in the Ar₃ position were tolerated. Addition of electron withdrawing groups appear to increase G protein signaling preference. For example, this trend was observed for 2d and 4l which had similar GTPγS potencies of 11 nM and 12 nM respectively. Compound 2d contained an electron withdrawing CF3 group and had a bias factor of 38 whereas 4l had an unsubstituted naphthyl group and only had a bias factor of 13. While bromo-substitution was preferred to chloro- and fluoro- substitution in terms of G protein EC₅₀ (Table 4), chloro-substitution further promotes G protein signaling preference, with the 4-chloro substituent (4d) having a bias factor of 79. Addition of a second electron withdrawing group, such as dichloro substitution (4j), increased G protein potency to 5.0 nM, our most potent compound, but did not increase the bias factor as calculated with the current parameters. Encouragingly, we found that compounds 4d, 4i, and 4j, showed improved potency in G protein signaling while maintaining G protein over βarrestin signaling preference (bias factors in the 70s).

2.3. Preliminary Docking Studies.

To gain preliminary information about the binding mode of triazole-containing KOR agonists, we docked triazole 1.1 into an active state salvinorin B methoxymethyl ether-bound KOR structure as determined by electron microscopy (PDB 8DZP, Figure 3A).[50] Apparent key binding features included two hydrogen bonds, from Tyr312 to N in the central ring (2.966 Å) and from Gln115 to the oxygen of the furan group (3.152 Å). Then, we docked triazoles bearing 1–3 methylene linkers at C-5 to determine if distinctions could be made between a non-binder (2a), a potent binder (2b), and a low-potency binder (2c) that could inform analogue design. All the compounds dock successfully to the KOR despite differences in activity, with only minor changes in predicted binding mode evident. At this stage, while competition experiments[39] support the view that triazoles exert their effects by binding to the orthosteric site of the KOR, additional pharmacological and structural biology studies are necessary to parse the specific interactions that modulate the degree of agonist binding and G protein-bias in order to fully make use of modeling studies.

Figure 3.

Structures of representative triazoles docked into the reported active structure of the KOR (PDB 8DZP)[50] A. Triazole 1.1 (green in all structures) B. Overlay of compound 2a (orange) with triazole 1.1. C. Overlay of compound 2b (pink) with triazole 1.1. D. Overlay of compound 2c (cyan) with triazole 1.1.

2.4. Microsomal stability.

Although active in vivo[51] triazole 1.1 has low microsomal stability as measured in vitro.[39] We considered the potential role of S-oxidation in metabolism of triazole 1.1. Thus, microsomal stability was determined using hepatic microsomes prepared from human and mouse liver as previously described.[52] We found that a representative carbon-linked triazole had similar microsomal stability (1.1 min for triazole 1.1 and 0.9 min for 2b, Table 8) suggesting that other sites in the molecule likely contribute to the rapid metabolic oxidation of the compound. Other changes to the appendages of the parent triazole (2b) also only led to slight changes in microsomal stability (Table 8, entries 1-11). Removal of the methylene linker on the 4-N position (entry 5) resulted in a compound of similar stability compared to that containing the methylene linker (entry 4). Complete removal of the carbon side chain (entry 19) resulted in a dramatic increase in microsomal stability indicating that the carbon linker is responsible for the low microsomal stability of the scaffold. We probed this hypothesis by designing analogues with various degrees of unsaturation as well as possible oxidative metabolites. Interestingly, the trans-double bond containing analogue (5d) was more metabolically stable than the corresponding saturated analogue (2b) (18.0 min and 0.9 min respectively). Modifications to the α (entries 14-16) and β (entries 17-18) positions resulted in increased half-life in human liver microsomes, but the half-lives remained similar in mouse liver microsomes. Since triazole 1.1 enters the brain at ~5X greater brain to plasma ratio[39] and it is active in vivo[9, 39], the importance of increasing microsomal stability is unclear. Nevertheless, these investigations probe the potential sites of metabolic liability and give insights for the future design of more metabolically stable analogues.

Table 8.

Microsomal Stability of Select Analogues

2.5. Chemistry.

The synthesis of 3,4,5 trisubstituted 1,2,4 triazoles was accomplished by modifications of established routes[53, 54] as shown in Scheme 1A. Building blocks for analogues without commercially available starting materials were synthesized via the Heck reaction (Scheme 2a), the Knoevenagel condensation (Scheme 2b), or the Grignard reaction (Scheme 2c).

Scheme 2. Representative Synthesis of Building Blocks^a.

^aReagents and conditions: (a) aryl bromide (1.0 equiv), acrylic acid (1.5 equiv), CsCO3 (1.2 equiv), tri-o-tolylphosphane (0.1 equiv), Pd(OAc)₂ (0.05 equiv), DMA (0.4 M), 17 h 120 °C; (b) 10a (1 equiv), Pd/C (0.1 equiv), THF (0.2 M), 17 h, rt; (c) Mg (1.0 equiv), THF (3.8 M), aryl bromide (1.0 equiv) in THF (0.9 M), rt, 17.5 h, then added dropwise to succinic anhydride (1.5 equiv) in THF (0.72 M), rt, 2h; (d) 10b (1.0 equiv), Pd/C (0.1 equiv), H₂, HOAc (0.3 M), 70 °C, 1 h; (e) aryl aldehyde (1.0 equiv), malonic acid (1.0 equiv), β-alanine (1.0 equiv), pyridine (2.2 M), 5 h, 110 °C; (f) 10c-10e (1 equiv), Pd/C (0.1 equiv), H₂, THF (0.2 M), 70 °C , 1 h.

Analogues 5b and 5c were synthesized via functionalizing the 3,4-disubstiuted triazole as described previously (Scheme 3).[38, 55] Once functionalized with an aldehyde, an Ohira–Bestmann alkynylation followed by a Sonogashira coupling afforded alkyne 5b. Reduction using Lindlar’s catalyst gave cis alkene 5c. The synthesis of trans-alkenes was achieved via Scheme 1B where the α-β unsaturated acid was coupled to the respective amine followed by thioamide formation and cyclization with hydrazide.

Synthesis of α oxygenated and α fluorinated analogues was achieved via addition of a Grignard reagent into aldehyde 16 (Scheme 4). The resulting alcohol (5e) was either oxidized to the ketone (5f) or fluorinated via DAST to the α monofluoride analogue (5g). Synthesis of the β-alcohol (5h) was achieved via Scheme 1 using commercially available 3-hydroxy-3-phenyl propanoic acid as the hydrazide precursor. A similar oxidation of the β-alcohol to afford the β-ketone was attempted. However, the desired product was not observed. Instead, the di-carbonyl was obtained. Alcohol 5h was fluorinated via DAST to give the β monofluoride analogue (5i).

3. Conclusions.

We have reported a novel series of G protein-biased, KOR agonists. Importantly, this series showed that the thioether sidechain was not necessary for KOR agonist activity. Substitution to the aromatic portion of the 5-position was well tolerated, though electron withdrawing groups were preferred. Various aromatic groups were tolerated in the 4N-position, although non-aromatic groups were not tolerated. Substitution at the 3-position was less tolerated as nitrogen was required at the 2-position of the aromatic ring. Finally, metabolic liabilities can be mitigated via substitution of the carbon linker chain itself. Unfortunately, these modifications also reduced potency. Particularly interesting analogues include 4j, our most potent compound in this series, 4d and 4i, our most biased compounds in this series, and 2e and 6e which are potential KOR partial agonists. Partial KOR agonists are of interest for the use of interest due to their potential to treat opioid use disorder.[56, 57] We continue to optimize this series as well as to look for additional chemotypes. Additionally, some analogues are undergoing further in vivo investigations, the results of which will be reported in due course.

4. Experimental Section

4.1. Chemistry

4.1.1. General Information.

All chemicals were used as received from a commercial source without further purification, unless otherwise noted. AgOBz was synthesized via the established method.[58] Thin-layer chromatography (TLC) was performed using commercial silica gel 250 μm coated glass-backed plates. Visualization was accomplished with UV light (254 nm) and an iodine vapor chamber. Purification was carried out on an automated flash chromatography/medium-pressure liquid chromatography (MPLC) system using normal-phase silica flash columns (4, 12, 24 or 40 g) or reverse-phase C-18 columns (12, 24, 40 g). ¹H and ¹³C NMR spectra were recorded on either a 400 MHz instrument with a dual carbon/proton probe or 600 MHz instrument with a dual carbon/proton cryoprobe instrument. Chemical shifts of ¹H and ¹³C NMR spectra are reported in parts per million (ppm) using the residual solvent signals as references. All coupling constants (J values) are reported in hertz (Hz). Multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), and multiplet (m). ¹⁹F NMR spectra were recorded on a 400 MHz instrument. Spectra are reported in ppm and referenced using a proton spectrum taken at the same time. IR spectra were acquired as films or solids as indicated on a Thermo Scientific Nicolet iS-5 FT-IR spectrometer. Melting points were determined using an Optimelt automatic digital melting point apparatus and are uncorrected. High-resolution mass spectrometry data was provided by University of North Carolina’s Department of Chemistry Mass Spectrometry Core Laboratory using a Q Exactive HF-X system. Compound purity was determined on a Waters Acquity Nano UPLC/MS instrument. The analytical method conditions included a Waters Acquity BEH C18 column (2.1 mm × 50 mm, 1.7 μm) and elution with a linear gradient of 5% acetonitrile in a formic acid aqueous solution (0.1% v/v) to 100% acetonitrile at 0.6 mL/min flow rate. Compound purity was measured on the basis of peak integration (area under the curve) from UV/Vis absorbance (at 214 nm), and compound identity was determined on the basis of mass analysis. Any compound with a measured UPLC purity of 100% was conservatively assigned a purity of “>99%”. All tested compounds were ≥95% pure except for 5c and 5e.

Synthesis of amides 7a-7w

N-(Furan-2-ylmethyl)picolinamide (7a).

2-Picolinic acid (150 mg, 1.2 mmol, 1.0 equiv), DMAP (15 mg, 0.12 mmol, 0.1 equiv), and CDI (296 mg, 1.8 mmol, 1.5 equiv) in THF (5.8 mL, 0.2 M) were stirred for 30 min. Furan-2-ylmethanamine (0.12 mL, 130 mg, 1.3 mmol, 1.1 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7a as a white solid (154.3 mg, 0.76 mmol, 62%). R_f = 0.26 (25% EtOAc, in hexanes); mp 104.3–106.6 °C. ¹H NMR (400 MHz, chloroform-d) δ 4.66 (d, J = 5.9 Hz, 2H), 6.27–6.30 (m, 1H), 6.31–6.34 (m, 1H), 7.37 (dd, J = 0.9, 1.9 Hz, 1H), 7.42 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.84 (td, J = 1.7, 7.7 Hz, 1H), 8.21 (dt, J = 1.1, 7.8 Hz, 1H), 8.33 (s, 1H), 8.53 (ddd, J = 0.9, 1.7, 4.8 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 36.4, 107.5, 110.4, 122.3, 126.2, 137.3, 142.3, 148.1, 149.7, 151.2, 164.1. IR (solid) 3341, 1658 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂O₂⁺ [M+H]⁺ 203.0815, found 203.0818. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)picolinamide (7b).

2-Picolinic acid (318 mg, 2.8 mmol, 1.0 equiv), DMAP (31 mg, 0.26 mmol, 0.1 equiv), and CDI (621 mg, 3.8 mmol, 1.5 equiv) in THF (12 mL, 0.2 molar) were stirred for 30 min. Thiophen-2-ylmethanamine (288 μL, 318 mg, 2.8 mmol, 1.1 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 50% EtOAc in hexanes) afforded 7b as a white solid (478.5 mg, 2.2 mmol, 86%). R_f = 0.29 (25% EtOAc, in hexanes); mp 104.6–107.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 4.84 (dd, J = 0.9, 6.0 Hz, 2H), 6.97 (dd, J = 3.5, 5.1 Hz, 1H), 7.06 (dq, J = 0.9, 3.5 Hz, 1H), 7.23 (dd, J = 1.2, 5.1 Hz, 1H), 7.44 (ddd, J = 1.3, 4.8, 7.6 Hz, 1H), 7.88 (td, J = 1.7, 7.7 Hz, 1H), 8.25 (dt, J = 1.1, 7.9 Hz, 1H), 8.44 (s, 1H), 8.54 (ddd, J = 0.9, 1.7, 4.8 Hz, 1H); ¹³C NMR (126 MHz, chloroform-d) δ 38.3, 122.6, 125.4, 126.3, 126.5, 127.1, 137.6, 140.9, 148.2, 149.8, 164.1. IR (solid) 3312, 1663 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂OS⁺ [M+H]⁺ 219.0587, found 219.0584. Purity (HPLC) >99%.

N-(Thiazol-2-ylmethyl)picolinamide (7c).

2-Picolinic acid (100 mg, 0.81 mmol, 1.0 equiv), DMAP (10 mg, 0.081 mmol, 0.1 equiv), and CDI (198 mg, 1.2 mmol, 1.5 equiv) in THF (4.0 mL, 0.2 M) were stirred for 1 h. Thiazol-2-ylmethanamine (85 μL, 102.0 mg, 0.89 mmol, 1.2 equiv) was added to the reaction, which was stirred for 4.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7c as yellow solid (159.8 mg, 0.73 mmol, 90%). R_f = 0.47 (75% EtOAc, in hexanes); mp 75.1–79.3°C. ¹H NMR (400 MHz, chloroform-d) δ 5.00 (d, J = 6.2 Hz, 2H), 7.29 (d, J = 3.3 Hz, 1H), 7.44 (ddd, J = 1.3, 4.8, 7.6 Hz, 1H), 7.74 (d, J = 3.3 Hz, 1H), 7.85 (td, J = 1.7, 7.7 Hz, 1H), 8.22 (dt, J = 1.1, 7.8 Hz, 1H), 8.56 (ddd, J = 0.9, 1.7, 4.8 Hz, 1H), 8.76 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 40.7, 120.0, 122.6, 126.7, 137.6, 141.8, 148.4, 149.3, 164.7, 167.9. IR (solid) 3304, 1657 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂OS⁺ [M+H]⁺ 220.0539, found 220.0540. Purity (HPLC) >99%.

N-Benzylpicolinamide (7d).

2-Picolinic acid (155 mg, 1.3 mmol, 1.0 equiv), DMAP (15 mg, 0.12 mmol, 0.1 equiv), and CDI (305 mg, 1.9 mmol, 1.5 equiv) in THF (6.0 mL, 0.2 M) were stirred for 30 min. Phenylmethanamine (151 μL, 148 mg, 1.4 mmol, 1.1 equiv) was added to the reaction, which was stirred for 3.5 h. Flash chromatography (100% hexanes to 50% EtOAc in hexanes) afforded 7d as a white solid (235.8 mg, 1.1 mmol, 88%). R_f = 0.28 (25% EtOAc, in hexanes); mp 95.2–99.1°C. ¹H NMR (400 MHz, chloroform-d) δ 4.67 (d, J = 6.1 Hz, 2H), 7.26–7.39 (complex, 5H), 7.42 (ddd, J = 1.3, 4.8, 7.6 Hz, 1H), 7.85 (td, J = 1.7, 7.7 Hz, 1H), 8.24 (dt, J = 1.1, 7.8 Hz, 1H), 8.37 (s, 1H), 8.52 (ddd, J = 0.9, 1.7, 4.7 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 43.6, 122.5, 126.3, 127.6, 128.0, 128.8, 137.5, 138.4, 148.2, 150.0, 164.4. IR (solid) 3299, 1656 cm⁻¹. HRMS calcd for C₁₃H₁₃N₂O⁺ [M+H]⁺ 213.1022, found 213.1015. Purity (HPLC) >99%.

N-Phenylpicolinamide (7e).

2-Picolinic acid (100 mg, 0.83 mmol, 1.0 equiv), DMAP (10 mg, 0.083 mmol, 0.1 equiv), and CDI (202 mg, 1.2 mmol, 1.5 equiv) in THF (4.0 mL, 0.2 M) were stirred for 30 min. Aniline (84 μL, 85 mg, 0.91 mmol, 1.1 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 80% EtOAc in hexanes) afforded 7e as a white solid (116.7 mg, 0.59 mmol, 71%). R_f = 0.41 (25% EtOAc, in hexanes); mp 97.2–102.9 °C. ¹H NMR (400 MHz, chloroform-d) δ 7.15 (tt, J = 1.2, 7.2 Hz, 1H), 7.35–7.42 (complex, 2H), 7.43–7.52 (m, 1H), 7.75–7.83 (complex, 2H), 7.90 (tt, J = 1.8, 7.7 Hz, 1H), 8.27–8.35 (m, 1H), 8.58–8.65 (m, 1H), 10.03 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 119.8, 122.5, 124.4, 126.6, 129.2, 137.8, 137.9, 148.1, 150.0, 162.1. IR (solid) 3332, 1666 cm⁻¹. HRMS calcd for C₁₂H₁₁N₂O⁺ [M+H]⁺ 199.0866, found 199.0860. Purity (HPLC) >99%.

N-(Pyridin-2-ylmethyl)picolinamide (7f).

2-Picolinic acid (151 mg, 1.2 mmol, 1.0 equiv), DMAP (15 mg, 0.012 mmol, 0.1 equiv), and CDI (299 mg, 1.8 mmol, 1.5 equiv) in THF (6.0 mL, 0.2 M) were stirred for 30 min. Pyridin-2-ylmethanamine (140 μL, 146 mg, 1.4 mmol, 1.1 equiv) was added to the reaction, which was stirred for 4 h at rt. Flash chromatography (100% DCM to 1% MeOH in DCM) afforded 7f as a yellow oil (133.4 mg, 0.62 mmol, 51%). R_f = 0.59 (5% MeOH, in DCM). ¹H NMR (400 MHz, chloroform-d) δ 4.82 (d, J = 5.7 Hz, 2H), 7.22 (dd, J = 5.2, 7.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.43 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.69 (td, J = 1.8, 7.6 Hz, 1H), 7.85 (td, J = 1.7, 7.7 Hz, 1H), 8.21 (dt, J = 1.1, 7.8 Hz, 1H), 8.60 (dddd, J = 1.0, 1.8, 3.9, 4.8 Hz, 2H), 8.94 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 44.7, 122.3, 122.4, 122.6, 126.4, 137.3, 137.4, 148.4, 149.0, 145.0, 157.0, 164.7. IR (neat) 3376, 1664 cm⁻¹. HRMS calcd for C₁₂H₁₂N₃O⁺ [M+H]⁺ 214.0975, found 214.0973; HPLC purity >99%.

N-(Pyridin-3-ylmethyl)picolinamide (7g).

2-Picolinic acid (103 mg, 0.84 mmol, 1.0 equiv), DMAP (10 mg, 0.084 mmol, 0.1 equiv), and CDI (203 mg, 1.2 mmol, 1.5 equiv) in THF (4 mL, 0.2 M) were stirred for 30 min. Pyridin-3-ylmethanamine (94 μL, 99 mg, 0.92 mmol, 1.2 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7g as a white solid (148.5 mg, 0.70 mmol, 83%). R_f = 0.43 (5% MeOH, in DCM); mp 74.2–80.1°C; ¹H NMR (400 MHz, chloroform-d) δ 4.67 (d, J = 6.3 Hz, 2H), 7.22–7.25 (m, 1H), 7.42 (ddd, J = 1.3, 4.8, 7.6 Hz, 1H), 7.69 (dt, J = 2.0, 7.9 Hz, 1H), 7.84 (td, J = 1.7, 7.7 Hz, 1H), 8.20 (dt, J = 1.1, 7.8 Hz, 1H), 8.45 (s, 1H), 8.49–8.54 (complex, 2H), 8.61 (d, J = 2.2 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 41.1, 122.5, 123.7, 126.6, 134.1, 135.8, 137.6, 148.3, 149.0, 149.4, 149.6, 164.6. IR (solid) 3316, 1659 cm⁻¹. HRMS calcd for C₁₂H₁₂N₃O⁺ [M+H]⁺ 214.0975, found 214.0973. Purity (HPLC) >99%.

N-(Pyridin-4-ylmethyl)picolinamide (7h).

2-Picolinic acid (104 mg, 0.84 mmol, 1.0 equiv), DMAP (10 mg, 0.084 mmol, 0.1 equiv), and CDI (205 mg, 1.3 mmol, 1.5 equiv) in THF (3.9 mL, 0.2 M) were stirred for 30 min. Pyridin-4-ylmethanamine (94 μL, 100 mg, 0.92 mmol, 1.2 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% DCM to 1% MeOH in DCM) afforded 7h as a yellow oil (174 mg, 0.82 mmol, 97%). R_f = 0.47 (5% MeOH, in DCM). ¹H NMR (400 MHz, chloroform-d) δ 4.69 (d, J = 6.4 Hz, 2H), 7.24–7.30 (complex, 2H), 7.46 (ddd, J = 1.3, 4.8, 7.6 Hz, 1H), 7.88 (td, J = 1.7, 7.7 Hz, 1H), 8.23 (dt, J = 1.1, 7.8 Hz, 1H), 8.50 (s, 1H), 8.53–8.59 (complex, 3H); ¹³C NMR (101 MHz, chloroform-d) δ 42.4, 122.4, 122.6, 126.6, 137.6, 147.5, 148.3, 149.5, 150.1, 164.8. IR (neat) 3323, 1660 cm⁻¹. HRMS calcd for C₁₂H₁₂N₃O⁺ [M+H]⁺ 214.0975, found 214.0967. Purity (HPLC) >99%.

N-(Cyclopropylmethyl)picolinamide (7i).

2-Picolinic acid (109, 0.89 mmol, 1.0 equiv), DMAP (11 mg, 0.089 mmol, 0.1 equiv), and CDI (216 mg, 1.3 mmol, 1.5 equiv) in THF (4.3 mL, 0.2 M) were stirred for 30 min. Cyclopropylmethanamine (85 μL, 69 mg, 0.98 mmol, 1.1 equiv) was added to the reaction, which was stirred for 4 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7i as a clear colorless oil (108.4, 0.62 mmol, 69%). R_f = 0.62 (50% EtOAc, in hexanes). ¹H NMR (400 MHz, chloroform-d) 0.23–0.36 (m, 2H), 0.49–0.62 (m, 2H), 1.00–1.15 (m, 1H), 3.34 (ddd, J = 1.3, 5.7, 7.1 Hz, 2H), 7.41 (ddt, J = 1.4, 4.8, 7.6 Hz, 1H), 7.84 (tt, J = 1.6, 7.7 Hz, 1H), 8.20 (dq, J = 1.2, 7.9 Hz, 1H), 8.13 (s, 1H), 8.52–8.59 (m, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 3.6, 10.9, 44.4, 122.4, 126.2, 137.5, 148.1, 150.2, 164.3. IR (neat) 1660, 1590, cm⁻¹. HRMS calcd for C₁₀H₁₃N₂O⁺ [M+H]⁺ 177.1022, found 177.1018. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)benzamide (7j).

Benzoic acid (213 mg, 1.7 mmol, 1.0 equiv), DMAP (21 mg, 0.17 mmol, 0.1 equiv), and CDI (424 mg, 2.6 mmol, 1.5 equiv) in THF (8.8 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (0.197 mL, 217 mg, 1.9 mmol, 1.1 equiv)was added to the reaction, which was stirred for 3 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7j as a white solid (305.9 mg, 1.4 mmol, 80%). R_f = 0.45 (25% EtOAc, in hexanes); mp 142.7–146.6°C. ¹H NMR (400 MHz, DMSO-d₆) δ 4.63 (dd, J = 0.9, 6.0 Hz, 2H), 6.96 (dd, J = 3.4, 5.1 Hz, 1H), 7.02 (dd, J = 1.2, 3.5 Hz, 1H), 7.35–7.41 (m, 1H), 7.43–7.50 (complex, 2H), 7.51–7.58 (m, 1H), 7.83–7.90 (complex, 2H), 9.13 (t, J = 5.9 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 37.8, 124.9, 125.4, 126.6, 127.2, 128.3, 131.3, 134.1, 142.7, 166.0. IR (solid) 3293, 1639 cm⁻¹. HRMS calcd for C₁₂H₁₂NOS⁺ [M+H]⁺ 218.0634, found 218.0632. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)nicotinamide (7k).

Nicotinic acid (177, 1.4 mmol, 1.0 equiv), DMAP (18 mg, 0.14 mmol, 0.1 equiv), and CDI (350 mg, 2.2 mmol, 1.5 equiv) in THF (6.0 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (162 μL, 179 mg, 1.6 mmol, 1.1 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) followed by flash chromatography (100% DCM to 1% MeOH in DCM) afforded 7k as a white solid (112.2, 0.51 mmol, 36%). R_f = 0.33 (100% EtOAc); mp 110.4–115.6°C. ¹H NMR (400 MHz, chloroform-d) δ 4.83 (d, J = 5.6 Hz, 2H), 6.97 (dd, J = 3.5, 5.1 Hz, 2H), 7.05–7.8 (m, 1H), 7.23–7.26 (m, 1H), 7.44 (ddd, J = 0.9, 4.9, 7.9 Hz, 1H), 8.23 (dt, J = 2.0, 8.0 Hz, 1H), 8.69 (dd, J = 1.7, 4.9 Hz, 1H), 9.10 (d, J = 2.3 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 39.0, 124.0, 125.7, 126.7, 127.2, 130.5, 136.6, 140.3, 147.3, 151.3, 164.9. IR (solid) 1656, 1629 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂OS⁺ [M+H]⁺ 219.0587, found 219.0584. Purity (HPLC) = 97%.

N-(Thiophen-2-ylmethyl)isonicotinamide (7l).

Isonicotinic acid (168 mg, 1.4 mmol, 1.0 equiv), DMAP (18.2 mg, 0.15 mmol, 0.1 equiv), and CDI (332 mg, 2.0 mmol, 1.5 equiv) in THF (6.5 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (210 μL, 232 mg, 2.0 mmol, 1.5 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 10% EtOAc in hexanes, followed by 100% DCM to 1% MeOH in DCM) afforded 7l as a white solid (134.8 mg, 0.62 mmol, 45%). R_f = 0.30 (5% MeOH in DCM); mp 145.7–150.8 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 4.65 (dd, J = 0.9, 5.9 Hz, 2H), 6.97 (dd, J = 3.4, 5.1 Hz, 1H), 7.04 (dt, J = 1.0, 3.2 Hz, 1H), 7.40 (dd, J = 1.3, 5.1 Hz, 1H), 7.72–7.79 (complex, 2H), 8.68–8.76 (complex, 2H), 9.43 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 37.8, 121.2, 125.2, 125.7, 126.7, 141.0, 141.9, 150.3, 164.5. IR (solid) 3307, 1644 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂OS⁺ [M+H]⁺ 219.0587, found 219.0583. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)pyrimidine-2-carboxamide (7m).

Pyrimidine-2-carboxylic acid (155 mg, 1.2 mmol, 1.0 equiv), DMAP (14 mg, 0.12 mmol, 0.1 equiv), and CDI (303 mg, 1.9 mmol, 1.5 equiv) in THF (6.0 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (191 μL, 211 mg, 1.9 mmol, 1.5 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 10% EtOAc in hexanes, followed by 100% DCM to 1% MeOH in DCM)) afforded 7m as a white solid (46.7 mg, 0.21 mmol, 17%). R_f = 0.49 (5% MeOH in DCM); mp 179.0–186.7 °C. ¹H NMR (400 MHz, chloroform-d) δ 4.88 (dd, J = 0.9, 5.9 Hz, 2H), 6.97 (dd, J = 3.5, 5.1 Hz, 1H), 7.04–7.09 (m, 1H), 7.24 (dd, J = 1.3, 5.1 Hz, 1H), 7.43 (t, J = 4.9 Hz, 1H), 8.31 (s, 1H), 8.86 (d, J = 4.9 Hz, 2H); ¹³C NMR (101 MHz, chloroform-d) δ 38.7, 122.7, 125.5, 126.6, 127.1, 140.2, 157.6, 157.6, 162.0. IR (solid) 3323, 1669 cm⁻¹. HRMS calcd for C₁₀H₁₀N₃OS⁺ [M+H]⁺ 220.0539, found 220.0539. Purity (HPLC) = 96%.

N-(Thiophen-2-ylmethyl)pyrimidine-4-carboxamide (7n).

Pyrimidine-4-carboxylic acid (180 mg, 1.4 mmol, 1.0 equiv), DMAP (18 mg, 0.14 mmol, 0.1 equiv), and CDI (352 mg, 2.2 mmol, 1.5 equiv) in THF (7.0 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (191 μL, 211 mg, 1.9 mmol, 1.5 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 50% EtOAc in hexanes) afforded 7n as a yellow oil (50.2 mg, 0.23 mmol, 16%). R_f = 0.39 (50% EtOAc in hexanes). ¹H NMR (400 MHz, DMSO-d₆) δ 4.65 (dd, J = 0.9, 6.3 Hz, 2H), 6.95 (dd, J = 3.4, 5.1 Hz, 1H), 7.03 (dq, J = 1.0, 3.1 Hz, 1H), 7.38 (dd, J = 1.3, 5.1 Hz, 1H), 8.04 (dd, J = 1.4, 5.0 Hz, 1H), 9.07 (d, J = 5.1 Hz, 1H), 9.33 (d, J = 1.4 Hz, 1H), 9.64 (t, J = 6.1 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 38.4, 118.8, 125.7, 126.6, 127.1, 140.0 156.1, 157.9, 159.4, 162.5. IR (neat) 3090, 1675 cm⁻¹. HRMS calcd for C₁₀H₁₀N₃OS⁺ [M+H]⁺ 220.0539, found 220.0537. Purity (HPLC) >99%.

3-Methyl-N-(thiophen-2-ylmethyl)picolinamide (7o).

3-Methylpicolinic acid (163 mg, 1.2 mmol, 1.0 equiv), DMAP (15 mg, 0.12 mmol, 0.1 equiv), and CDI (290 mg, 1.8 mmol, 1.5 equiv) in THF (6.0 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (0.18 mL, 202 mg, 1.8 mmol, 1.5 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 30% EtOAc in hexanes) afforded 7o as a yellow oil (169.8 mg, 0.73 mmol, 61%). R_f = 0.36 (25% EtOAc, in hexanes). ¹H NMR (400 MHz, chloroform-d) δ 2.77 (s, 3H), 4.79 (dd, J = 0.9, 6.0 Hz, 2H), 6.96 (dd, J = 3.4, 5.1 Hz, 1H), 7.05 (dt, J = 1.0, 3.2 Hz, 1H), 7.22 (dd, J = 1.2, 5.1 Hz, 1H), 7.30 (dd, J = 4.6, 7.8 Hz, 1H), 7.59 (ddd, J = 0.8, 1.7, 7.7 Hz, 1H), 8.36 (ddd, J = 0.7, 1.6, 4.6 Hz, 1H), 8.50 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 20.7, 38.2 125.2, 125.9, 126.1, 127.0, 135.8, 141.0, 141.4, 145.6, 147.1, 165.7. IR (neat) 3376, 1663 cm⁻¹. HRMS calcd for C₁₂H₁₃N₂OS⁺ [M+H]⁺ 233.0743, found 233.0741. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)-1-naphthamide (7p).

1-Naphthoic acid (270 mg, 1.6 mmol, 1.0 equiv), DMAP (19 mg, 0.16 mmol, 0.1 equiv), and CDI (382 mg, 2.4 mmol, 1.5 equiv) in THF (7.5 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (0.24 mL, 267 mg, 2.4 mmol, 1.5 equiv) was added to the reaction, which was stirred for 4 h at rt. Flash chromatography (100% hexanes to 25% EtOAc in hexanes) afforded 7p as a white solid (273.0 mg, 1.0 mmol, 65%). R_f = 0.39 (25% EtOAc, in hexanes); mp 165.4–170.5 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 4.70 (d, J = 6.0 Hz, 2H), 7.00 (dd, J = 3.4, 5.1 Hz, 1H), 7.07 (dd, J = 1.2, 3.5 Hz, 1H), 7.43 (dd, J = 1.2, 5.1 Hz, 1H), 7.5 7.65 (complex, 4H), 7.92–7.99 (m, 1H), 8.02 (d, J = 8.1 Hz, 1H), 8.17–8.25 (m, 1H), 9.19 (t, J = 6.0 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 37.7, 125.0, 125.0, 125.2, 125.29, 125.33, 126.2, 126.71, 126.73, 128.2, 129.8, 129.9, 133.1, 134.4, 142.7, 168.4. IR (solid) 3265, 1631. HRMS calcd for C₁₆H₁₄NOS⁺ [M+H]⁺ 268.0791, found 268.0789. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)-2-naphthamide (7q).

2-Naphthoic acid (149 mg, 1.0 mmol, 0.86 equiv), DMAP (10 mg, 0.086 mmol, 0.1 equiv), and CDI (210 mg, 1.3 mmol, 1.5 equiv) in THF (4.5 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (0.13 mL, 147 mg, 1.3 mmol, 1.5 equiv) was added to the reaction, which was stirred for 3 h at rt. Flash chromatography (100% hexanes to 50% EtOAc in hexanes) afforded 7q as a white solid (138.2 mg, 0.52 mmol, 60%). R_f = 0.33 (25% EtOAc, in hexanes); mp 162.4–165.8°C. ¹ NMR (400 MHz, chloroform-d) δ 4.88 (dd, J = 0.9, 5.6 Hz, 2H), 6.58 (s, 1H), 7.00 (dd, J = 3.5, 5.1 Hz, 1H), 7.09 (dt, J = 1.0, 3.5 Hz, 1H), 7.27 (dd, J = 1.2, 5.1 Hz, 1H), 7.49–7.61 (complex, 2H), 7.81–7.95 (complex, 5H), 8.28 – 8.33 (m, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 39.1, 123.7, 125.6, 126.5, 127.0, 127.2, 127.7, 127.89, 127.91, 128.7, 129.1, 131.5, 132.8, 135.0, 140.9, 167.3. IR (solid) 3294, 1635 cm⁻¹. HRMS calcd for C₁₆H₁₄NOS⁺ [M+H]⁺ 268.0791, found 268.0783; Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)quinoline-2-carboxamide (7r).

Quinoline-2-carboxylic acid (155 mg, 0.87 mmol, 1.0 equiv), DMAP (12 mg, 0.10 mmol, 0.1 equiv), and CDI (211 mg, 1.3 mmol, 1.5 equiv) in THF (4.5 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (134 μL, 147 mg, 1.3 mmol, 1.5 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 30% EtOAc in Hexanes) afforded 7r as a white solid (204.4 mg, 0.76 mmol, 88%). R_f = 0.49 (25% EtOAc in Hex); mp 123.0–125.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 4.72 (d, J = 6.3 Hz, 2H), 6.90–7.01 (m, 1H), 7.07 (dd, J = 1.2, 3.5 Hz, 1H), 7.39 (dd, J = 1.3, 5.1 Hz, 1H), 7.73 (ddd, J = 1.3, 6.9, 8.2 Hz, 1H), 7.88 (ddd, J = 1.5, 6.8, 8.4 Hz, 1H), 8.11 (dd, J = 8.3, 16.4 Hz, 2H), 8.18 (d, J = 8.5 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H), 9.50 (t, J = 6.4 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 38.5, 119.1, 125.4, 126.3, 127.1, 127.9, 128.1, 129.5, 129.8, 130.3, 137.7, 141.1, 146.6, 149.6, 164.4. IR (solid) 3389, 1688 cm⁻¹. HRMS calcd for C₁₅H₁₃N₂OS⁺ [M+H]⁺ 269.0743, found 269.0737. Purity (HPLC) >99%.

3-(4-Methyl-3-(trifluoromethyl)phenyl)N-(thiophen-2-ylmethyl)propanamide (7s).

3-(4-Methyl-3-(trifluoromethyl)phenyl)propanoic acid (11a) (151 mg , 0.65 mmol, 1.0 equiv), DMAP (7.9 mg, 0.065 mmol, 0.1 equiv), and CDI (158 mg, 0.98 mmol, 1.5 equiv) in THF (3.1 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (73 μL, 81 mg, 0.72 mmol, 1.1 equiv) was added to the reaction which stirred for 4 h. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7s as a white solid (195.9 mg, 0.69 mmol, 92%). R_f = 0.56 (50% EtOAc, in hexanes); mp 94.6–99.3°C. ¹ NMR (400 MHz, chloroform-d) δ 2.43 (d, J = 1.9 Hz, 3H), 2.45–2.51 (complex, 2H), 3.00 (t, J = 7.6 Hz, 2H), 4.58 (dd, J = 0.8, 5.6 Hz, 2H), 5.67 (s, 1H), 6.88–6.90 (m, 1H), 6.91–6.95 (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 1.3, 5.1 Hz, 1H), 7.22–7.26 (m, 1H), 7.42 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.2 Hz), 31.0, 38.2, 38.4, 124.7 (q, J = 273.6 Hz), 125.4, 125.7 (q, J = 5.5 Hz), 126.2, 127.0, 129.1 (q, J = 29.7 Hz), 131.8, 132.3, 134.6, 138.6, 140.8, 171.4; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 3299, 1639 cm⁻¹. HRMS calcd for C₁₆H₁₇F₃NOS⁺ [M+H]⁺ 328.0977, found 328.0972. Purity (HPLC) >99%.

3-Phenyl-N-(thiophen-2-ylmethyl)propanamide (7t).

3-Phenylpropanoic acid (176 mg, 1.2 mmol, 1.0 equiv), DMAP (14 mg, 0.12 mmol, 0.1 equiv), and CDI (285 mg, 1.8 mmol, 1.5 equiv) in THF (6.1 mL, 0.2 molar) were stirred for 30 min. Thiophen-2-ylmethanamine (132 μL, 146 mg, 1.3 mmol, 1.2 equiv) was added to the reaction, which was stirred for 3.5 hours at rt. Flash chromatography (100% hexanes to 80% EtOAc in hexanes) afforded 7t as a white solid (241.0 mg, 0.98 mmol, 84%). R_f = 0.21 (25% EtOAc, in hexanes); mp 95.9–101.0°C. ¹H NMR(400 MHz, chloroform-d) δ 2.49 (dd, J = 7.0, 8.4 Hz, 2H), 2.98 (t, J = 7.7 Hz, 2H), 4.57 (dd, J = 0.8, 5.7 Hz, 2H), 5.67 (s, 1H), 6.87–6.89 (m, 1H), 6.92 (dd, J = 3.5, 5.1 Hz, 1H), 7.16–7.22 (complex, 4H), 7.25 (d, J = 0.9 Hz, 1H), 7.26–7.29 (m, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 31.7, 38.4, 38.5, 125.3, 126.2, 126.4, 127.0, 128.5, 128.7, 140.9, 140.9, 171.8. IR (solid) 3288, 1630 cm⁻¹. HRMS calcd for C₁₄H₁₆NOS⁺ [M+H]⁺ 246.0947, found 246.0940. Purity (HPLC) >99%.

(E)-N-(Furan-2-ylmethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)acrylamide (7u).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)acrylic acid (10a) (155 mg, 0.67 mmol, 1.0 equiv), DMAP (8.2 mg, 0.067 mmol, 0.1 equiv), and CDI (164 mg, 1.0 mmol, 1.5 equiv) in THF (3.0 mL, 0.2 M) were stirred for 30 min. Furan-2-ylmethanamine (31 μL, 34 mg, 0.35 mmol, 1.1 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7u as a white solid (95 mg, 0.31 mmol, 45%). R_f = 0.24 (25% EtOAc, in hexanes); mp 137.9–139.8°C. ¹H NMR (400 MHz, chloroform-d) δ 2.48 (q, J = 1.9 Hz, 3H), 4.57 (d, J = 5.8 Hz, 2H), 6.04 (s, 1H), 6.27 (dq, J = 0.8, 3.3 Hz, 1H), 6.33 (dd, J = 1.9, 3.2 Hz, 1H), 6.42 (d, J = 15.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 0.9, 1.9 Hz, 1H), 7.51 (dd, J = 1.7, 7.7 Hz, 1H), 7.63 (d, J = 15.6 Hz, 1H), 7.70–7.73 (m, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.4 (q, J = 2.2 Hz), 36.9, 107.8, 110.7, 121.1, 124.3 (q, J = 124.0 Hz), 124.9 (q, J = 5.6 Hz), 129.6 (q, J = 30.1 Hz), 131.0, 132.6, 132.8, 138.4, 140.2, 142.5, 151.1, 165.3; ¹⁹F NMR(376 MHz, chloroform-d) δ −62.0. IR (solid) 3253, 1655 cm⁻¹. HRMS calcd for C₁₆H₁₅F₃NO₂⁺ [M+H]⁺ 310.1049, found 310.1047. Purity (HPLC) >99%.

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiophen-2-ylmethyl)acrylamide (7v).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)acrylic acid (10a) (151 mg, 0.66 mmol, 1.0 equiv), DMAP (8.0 mg, 0.066 mmol, 0.1 equiv), and CDI (160 mg, 0.98 mmol, 1.5 equiv) in THF (3.0 mL, 0.2 M) were stirred for 30 min. Thiophen-2-ylmethanamine (69 μL, 76 mg, 0.67 mmol, 1.2 equiv) was added to the reaction, which was stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7v as a white solid (63.7 mg, 0.20 mmol, 30%). R_f = 0.27 (25% EtOAc, in hexanes); mp 142.2–145.2°C; ¹H NMR (600 MHz, chloroform-d) δ 2.49 (q, J = 1.9 Hz, 3H), 4.73–4.77 (complex, 2H), 5.96 (d, J = 5.8 Hz, 1H), 6.40 (d, J = 15.6 Hz, 1H), 6.97 (dd, J = 3.4, 5.1 Hz, 1H), 7.02 (dd, J = 1.2, 3.4 Hz, 1H), 7.24 (dd, J = 1.3, 5.1 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.52 (dd, J = 1.9, 7.9 Hz, 1H), 7.65 (d, J = 15.6 Hz, 1H), 7.73 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.4 (d, J = 2.3 Hz), 38.7, 121.0, 124.3 (q, J = 274.2 Hz), 124.9 (q, J = 5.5 Hz), 125.6, 126.5, 127.1, 129.7 (q, J = 30.1 Hz), 131.0, 132.7, 132.7, 138.5, 140.3, 140.6, 165.2; ¹⁹F NMR (376 MHz, chloroform-d) δ −62.0. IR (solid) 3261, 1654 cm⁻¹. HRMS calcd for C₁₆H₁₅F₃NOS⁺ [M+H]⁺ 326.0821, found 326.0816. Purity (HPLC) >99%.

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiazol-2-ylmethyl)acrylamide (7w).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)acrylic acid (10a) (151 mg, 0.66 mmol, 1.0 equiv), DMAP (8.0 mg, 0.066 mmol, 0.1 equiv), and CDI (160 mg, 0.99 mmol, 1.5 equiv) in THF (3.0 mL, 0.2 M) were stirred for 30 min. Thiazol-2-ylmethanamine (69 μL, 0.83 mg, 0.72 mmol, 1.1 equiv) was added to the reaction which stirred for 3.5 h at rt. Flash chromatography (100% hexanes to 100% EtOAc) afforded 7w as a yellow solid (131.4 mg, 0.40 mmol, 61%). R_f = 0.40 (75% EtOAc, in hexanes); mp 137.6–138.9°C. ¹H NMR (400 MHz, chloroform-d) δ 2.50 (d, J = 1.9 Hz, 3H), 4.91 (d, J = 5.7 Hz, 2H), 6.48 (d, J = 15.6 Hz, 1H), 6.53 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 15.6 Hz, 1H), 7.74 (d, J = 3.2 Hz, 2H); ¹³C NMR (151 MHz, chloroform-d) 19.4 (d, J = 2.1 Hz), 40.6, 120.4, 120.6, 124.3 (q, J = 274.0 Hz), 125.2 (q, J = 5.5 Hz), 129.7 (q, J = 29.9 Hz), 131.0, 132.6, 132.7, 138.7, 140.8, 140.9, 165.7, 167.8; ¹⁹F NMR (376 MHz, chloroform-d) δ −62.0. IR (solid) 3241, 1676 cm⁻¹. HRMS calcd for C₁₅H₁₄F₃N₂OS⁺ [M+H]⁺ 327.0773, found 327.0771. Purity (HPLC) = 91%.

Synthesis of thioamides 8a-8w

N-(Furan-2-ylmethyl)pyridine-2-carbothioamide (8a).

N-(Furan-2-ylmethyl)picolinamide (7a) (170 mg, 0.84 mmol, 1.0 equiv), Lawesson’s reagent (376 mg, 1.0 mmol, 1.2 equiv), and toluene (4.3 mL, 0.2 M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 25% EtOAc in hexances) to afford 8a as a yellow solid (105.1 mg, 0.48 mmol, 57%). R_f = 0.46 (10% EtOAc, in hexanes); mp 63.7–67.0 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.04 (d, J = 5.3 Hz, 2H), 6.38 (dd, J = 1.9, 3.3 Hz, 1H), 6.39–6.42 (m, 1H), 7.39–7.47 (complex, 2H), 7.84 (td, J = 1.7, 7.8 Hz, 1H), 8.48 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H), 8.70 (dt, J = 1.1, 8.0 Hz, 1H), 10.34 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 42.9, 109.0, 110.7, 125.0, 126.3, 137.4, 142.9, 147.1, 149.5, 151.0, 191.0 IR (solid) 3226, 1512 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂OS⁺ [M+H]⁺ 219.0587, found 219.0590. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b).

N-(Thiophen-2-ylmethyl)picolinamide (7b) (100 mg, 0.46 mmol, 1.0 equiv), Lawesson’s reagent (206 mg, 0.55 mmol, 1.2 equiv) and toluene (2.3 mL, 0.2M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes) to afford 8b as a yellow solid (91.7 mg, 0.39 mmol, 85%). R_f = 0.62 (25% EtOAc, in hexanes); mp 72.5–75.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.22 (dd, J = 0.8, 5.5 Hz, 2H), 7.01 (dd, J = 3.5, 5.1 Hz, 1H), 7.14 (dq, J = 0.9, 3.5 Hz, 1H), 7.28 (dd, J = 1.2, 5.1 Hz, 1H), 7.42 (ddd, J = 1.2, 4.7, 7.6 Hz, 1H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.46 (ddd, J = 0.9, 1.8, 4.7 Hz, 1H), 8.71 (dt, J = 1.1, 8.0 Hz, 1H), 10.33 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 44.5, 125.1, 126.0, 126.3, 127.2, 127.4, 137.4, 138.5, 147.1, 151.0, 190.8. IR (solid) 3238, 1537 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂S2⁺ [M+H]⁺ 235.0358, found 235.0358. Purity (HPLC) >99%.

N-(Thiazol-2-ylmethyl)pyridine-2-carbothioamide (8c).

N-(Thiazol-2-ylmethyl)picolinamide (7c) (291 mg, 1.3 mmol, 1.0 equiv), Lawesson’s reagent (600 mg, 1.6 mmol, 1.2 equiv), and toluene (6.8 mL, 0.2 M) were allowed to reflux for 2 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 80% EtOAc in hexanes) to afford 8c as a yellow solid (95.4 mg, 0.40 mmol, 30%). R_f = 0.44 (50% EtOAc, in hexanes); mp 99.4–104.1°C. ¹H NMR (400 MHz, chloroform-d) δ 5.09 (d, J = 4.9 Hz, 2H), 7.24–7.32 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 3.1 Hz, 1H), 7.74 (td, J = 1.8, 7.7 Hz, 1H), 7.94 (d, J = 3.1 Hz, 1H), 8.61–8.67 (m, 1H), 10.39 (s, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 49.8, 122.6, 123.1, 126.9, 137.4, 144.1, 149.2, 154.2, 169.0, 184.2. IR (solid) 3259, 1595 cm⁻¹. HRMS calcd for C₁₀H₁₀N₃S₂⁺ [M+H]⁺ 236.0311, found 236.0306. Purity (HPLC) >99%.

N-Benzylpyridine-2-carbothioamide (8d).

N-Benzylpicolinamide (7d) (179 mg, 0.84 mmol, 1.0 equiv), Lawesson’s reagent (372 mg, 1.0 mmol, 1.2 equiv), and toluene (4.3 mL, 0.2 M) were allowed to reflux for 2 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 25% EtOAc in hexanes) to afford 8d as a yellow solid (175.2 mg, 0.77 mmol, 91%). R_f = 0.11 (10% EtOAc, in hexanes); mp 78.2–82.2 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.06 (d, J = 5.6 Hz, 2H), 7.30–7.46 (complex, 6H), 7.84 (td, J = 1.8, 7.8 Hz, 1H), 8.46 (ddd, J = 0.9, 1.7, 4.7 Hz, 1H), 8.74 (dt, J = 1.1, 8.0 Hz, 1H), 10.37 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 50.1, 125.2, 126.2, 128.1, 128.5, 129.1, 136.5, 137.5, 147.0, 151.1, 191.0. IR (solid) 3235, 1512 cm⁻¹. HRMS calcd for C₁₃H₁₃N₂S⁺ [M+H]⁺ 229.0794, found 229.0786. Purity (HPLC) >99%.

N-Phenylpyridine-2-carbothioamide (8e).

N-Phenylpicolinamide (7e) (154 mg, 0.78 mmol, 1.0 equiv), Lawesson’s reagent (299 mg, 0.80 mmol, 1.0 equiv), and toluene (3.7 mL, 0.2 M) were allowed to reflux for 2.5 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes) to afford 8e as a yellow oil (131.3 mg, 0.61 mmol, 79%). R_f = 0.55 (25% EtOAc, in hexanes). ¹H NMR (400 MHz, chloroform-d) δ 7.27–7.33 (m, 1H), 7.42–7.52 (complex, 3H), 7.91 (td, J = 1.8, 7.8 Hz, 1H), 8.05–8.11 (complex, 2H), 8.55 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H), 8.81 (dt, J = 1.1, 8.0 Hz, 1H), 12.09 (s, 1H); ¹³C NMR(101 MHz, chloroform-d) δ 122.9, 125.0, 126.2, 126.7, 129.0, 137.7, 138.9, 146.6, 151.6, 188.0. IR (neat) 3208, 1586 cm⁻¹. HRMS calcd for C₁₂H₁₁N₂S⁺ [M+H]⁺ 215.0638, found 215.0636. Purity (HPLC) >99%.

N-(Pyridin-2-ylmethyl)pyridine-2-carbothioamide (8f).

N-(Pyridin-2-ylmethyl)picolinamide (7f) (161 mg, 0.76 mmol, 1.0 equiv), Lawesson’s reagent (363 mg, 0.96 mmol, 1.3 equiv), and toluene (3.8 mL, 0.2 M) were allowed to reflux for 24 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes) to afford 8f as a yellow oil (34.1 mg, 0.15 mmol, 20%). Due to low stability, the oil was used in the next step without further characterization.

N-(Pyridin-3-ylmethyl)pyridine-2-carbothioamide (8g).

N-(Pyridin-3-ylmethyl)picolinamide (7g) (83 mg, 0.39 mmol, 1.0 equiv), Lawesson’s reagent (169 mg, 0.45 mmol, 1.2 equiv), and toluene (2.5 mL, 0.2 M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hex to 100% EtOAc) to afford 8g as a yellow oil (51.7 mg, 0.22 mmol, 58%). R_f = 0.50 (5% MeOH, in DCM). ¹H NMR (400 MHz, chloroform-d) δ 5.11 (d, J = 5.8 Hz, 2H), 7.28–7.34 (m, 1H), 7.44 (ddd, J = 1.2, 4.7, 7.6 Hz, 1H), 7.77 (dd, J = 2.2, 7.9 Hz, 1H), 7.85 (td, J = 1.8, 7.8 Hz, 1H), 8.47 (ddd, J = 0.9, 1.8, 4.7 Hz, 1H), 8.58 (dd, J = 1.6, 4.8 Hz, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.71 (dt, J = 1.0, 8.0 Hz, 1H), 10.44 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 47.0, 123.8, 125.1, 126.4, 132.5, 136.2, 137.5, 147.1, 149.2, 149.5, 150.9, 191.8. IR (neat) 3256, 1577 cm⁻¹. HRMS calcd for C₁₂H₁₂N₃S⁺ [M+H]⁺ 230.0746, found 230.0744. Purity (HPLC) >99%.

N-(Pyridin-4-ylmethyl)pyridine-2-carbothioamide (8h).

N-(Pyridin-4-ylmethyl)picolinamide (7h) (171 mg, 0.80 mmol, 1.0 equiv), Lawesson’s reagent (359 mg, 0.96 mmol, 1.2 equiv), and toluene (4.0 mL, 0.2 M) were allowed to reflux for 1.5 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes, followed by 100% DCM to 0.8% MeOH in DCM) to afford 8h as a yellow solid (34.7 mg, 0.15 mmol, 19%). R_f = 0.64 (5% MeOH, in DCM); mp 87.0–92.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.14 (d, J = 6.0 Hz, 2H), 7.31 (d, J = 5.2 Hz, 2H), 7.47 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.87 (td, J = 1.7, 7.8 Hz, 1H), 8.48–8.53 (m, 1H), 8.60 (d, J = 5.0 Hz, 2H), 8.71 (d, J = 8.0 Hz, 1H), 10.54 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 48.2, 122.7, 125.2, 126.5, 137.6, 145.9, 147.2, 150.1, 150.8, 192.4. IR (solid) 3234, 1600 cm⁻¹. HRMS calcd for C₁₂H₁₂N₃S⁺ [M+H]⁺ 230.0746, found 230.0739. Purity (HPLC) >99%.

N-(Cyclopropylmethyl)pyridine-2-carbothioamide (8i).

N-(Cyclopropylmethyl)picolinamide (7i) (268 mg, 1.52 mmol, 1.0 equiv), Lawesson’s reagent (555 mg, 1.5 mmol, 1.0 equiv), and toluene (7.7 mL, 0.2 M) were allowed to reflux for 3 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes) to afford 8i as a yellow solid (244.9 mg, 1.3 mmol, 84%). R_f = 0.57 (25% EtOAc, in hexanes); mp 68.2–70.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 0.34–0.43 (complex, 2H), 0.62–0.69 (complex, 2H), 1.19–1.30 (m, 1H), 3.70 (dd, J = 5.2, 7.3 Hz, 2H), 7.44 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.85 (td, J = 1.8, 7.8 Hz, 1H), 8.52 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H), 8.72 (dt, J = 1.1, 8.0 Hz, 1H), 10.25 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 3.9, 9.6, 51.2, 125.2, 126.2, 137.7, 146.7, 151.1, 190.2. IR (solid) 3280, 1517 cm⁻¹. HRMS calcd for C₁₀H₁₃N₂S⁺ [M+H]⁺ 193.0794, found 193.0790. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)benzothioamide (8j).

N-(Thiophen-2-ylmethyl)benzamide (7j) (167 mg, 0.77 mmol, 1.0 equiv), Lawesson’s reagent (340 mg, 0.91 mmol, 1.2 equiv), and toluene (3.9 mL, 0.2 M) were allowed to reflux for 5 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 70% EtOAc in hexanes) to afford 8j as a yellow solid (172.3 mg, 0.74 mmol, 96%). R_f = 0.45 (25% EtOAc, in hexanes); mp 94.1–97.3 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.14–5.20 (complex, 2H), 7.02 (ddd, J = 1.0, 3.5, 5.0 Hz, 1H), 7.10–7.16 (m, 1H), 7.30 (dt, J = 1.3, 5.1 Hz, 1H), 7.34–7.42 (complex, 2H), 7.42–7.51 (m, 1H), 7.64–7.79 (complex, 3H); ¹³C NMR (101 MHz, chloroform-d) δ 45.6, 126.3, 126.9, 127.3, 127.7, 128.7, 131.4, 138.2, 141.5, 199.0. IR (solid) 3308, 1538 cm⁻¹. HRMS calcd for C₁₂H₁₂N₂S⁺ [M+H]⁺ 234.0406, found 234.0402. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)pyridine-3-carbothioamide (8k).

N-(Thiophen-2-ylmethyl)nicotinamide (7k) (161 mg, 0.74 mmol, 1.0 equiv), Lawesson’s reagent (316 mg, 0.85 mmol, 1.1 equiv), and toluene (3.7 mL, 0.2 M) were allowed to reflux for 2 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 8k as ayellow solid (30.0 mg, 0.13 mmol, 17%). R_f = 0.38 (75% EtOAc, in hexanes); mp 124.7–128.3 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.18 (d, J = 5.1 Hz, 2H), 7.00 (dd, J = 3.5, 5.2 Hz, 1H), 7.12–7.18 (m, 1H), 7.28 (dd, J = 1.2, 5.1 Hz, 1H), 7.42 (t, J = 6.2 Hz, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.68 (s, 1H), 8.96 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 45.4, 124.1, 126.3, 127.3, 128.0, 137.8, 137.9, 138.2, 144.8, 149.5, 194.5. IR (solid) 3152, 1585 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂S⁺ [M+H]⁺ 235.0358, found 235.0354. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)pyridine-4-carbothioamide (8l).

N-(Thiophen-2-ylmethyl)isonicotinamide (7l) (135 mg, 0.62 mmol, 1.0 equiv), Lawesson’s reagent (279 mg, 0.75 mmol, 1.2 equiv) and toluene (3.0 mL, 0.2M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 8l as a yellow solid (43.8 mg, 0.19 mmol, 30%). R_f = 0.44 (100% EtOAc); mp 208.3–216.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.16 (d, J = 5.1 Hz, 2H), 7.03 (dd, J = 3.5, 5.2 Hz, 1H), 7.12–7.16 (m, 1H), 7.32 (dd, J = 1.1, 5.2 Hz, 1H), 7.55–7.59 (complex, 2H), 7.83 (s, 1H), 8.64–8.67 (complex, 2H); ¹³C NMR (101 MHz, chloroform-d) δ 45.6, 120.7, 126.6, 127.4, 128.0, 137.5, 148.1, 150.4, 196.2. IR (solid) 3173, 1594 cm⁻¹. HRMS calcd for C₁₁H₁₁N₂S₂⁺ [M+H]⁺ 235.0358, found 235.0354. Purity (HPLC) = 98%.

N-(Thiophen-2-ylmethyl)pyrimidine-2-carbothioamide (8m).

N-(Thiophen-2-ylmethyl)pyrimidine-2-carboxamide (7m) (141 mg, 0.64 mmol, 1.0 equiv), Lawesson’s reagent (296 mg, 0.79 mmol, 1.2 equiv) and toluene (3.2 mL, 0.2M) were allowed to reflux for 1.5 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 8m as a yellow oil (88.8 mg, 0.38 mmol, 59%). R_f = 0.48 (5% MeOH, in DCM). ¹H NMR (400 MHz, chloroform-d) δ 5.23 (dd, J = 0.8, 5.4 Hz, 2H), 7.02 (dd, J = 3.5, 5.1 Hz, 1H), 7.16 (ddd, J = 0.7, 1.3, 3.5 Hz, 1H), 7.30 (dd, J = 1.2, 5.1 Hz, 1H), 7.43 (t, J = 4.8 Hz, 1H), 8.87 (d, J = 4.8 Hz, 2H), 10.13 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 45.0, 122.3, 126.1, 127.2, 127.6, 138.0, 157.4, 157.5, 189.3. IR (neat) 3294, 1562 cm⁻¹. HRMS calcd for C₁₀H₁₀N₃S₂⁺ [M+H]⁺ 236.0311, found 236.0306. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)pyrimidine-4-carbothioamide (8n).

N-(Thiophen-2-ylmethyl)pyrimidine-4-carboxamide (7n) (178 mg, 0.81 mmol, 1.0 equiv), Lawesson’s reagent (370 mg, 1.0 mmol, 1.2 equiv) and toluene (3.8 mL, 0.2M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 30% EtOAc in hexanes, followed by 100% DCM to 100% EtOAc) to afford 8n as a yellow solid (84.3 mg, 0.36 mmol, 44%). R_f = 0.58 (05% EtOAc, in hexanes); mp 98.6–106.1 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.20 (dd, J = 0.8, 5.5 Hz, 2H), 7.03 (dd, J = 3.5, 5.1 Hz, 1H), 7.15 (dq, J = 0.9, 3.5 Hz, 1H), 7.31 (dd, J = 1.2, 5.1 Hz, 1H), 8.56 (dd, J = 1.4, 5.2 Hz, 1H), 8.94 (d, J = 5.2 Hz, 1H), 9.16 (d, J = 1.4 Hz, 1H), 10.19 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) 44.6, 120.7, 126.3, 127.3, 127.7, 137.7, 156.4, 157.1, 159.0, 188.6. IR (solid) 3209, 1577 cm⁻¹ HRMS calcd for C₁₀H₁₀N₃S₂⁺ [M+H]⁺ 236.0311, found 236.0311. Purity (HPLC) = 98%.

3-Methyl-N-(thiophen-2-ylmethyl)pyridine-2-carbothioamide (8o)

3-Methyl-N-(Thiophen-2-ylmethyl)picolinamide (7o) (163 mg, 0.70 mmol, 1.0 equiv), Lawesson’s reagent (331 mg, 0.89 mmol, 1.3 equiv), and toluene (3.5 mL, 0.2 M) were allowed to reflux for 1.5 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes) to afford 8o as a yellow oil (66.5 mg, 0.27 mmol, 38%). R_f = 0.62 (50% EtOAc, in hexanes). ¹H NMR (400 MHz, DMSO-d₆) δ 2.26 (s, 3H), 5.11 (dd, J = 0.8, 5.9 Hz, 2H), 7.00 (dd, J = 3.5, 5.1 Hz, 1H), 7.12 (dd, J = 1.1, 3.5 Hz, 1H), 7.30 (dd, J = 4.8, 7.7 Hz, 1H), 7.44 (dd, J = 1.3, 5.1 Hz, 1H), 7.66 (ddd, J = 0.8, 1.8, 7.6 Hz, 1H), 8.30–8.36 (m, 1H), 10.98 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 18.1, 42.6, 123.5, 125.8, 126.5, 127.0, 128.9, 138.7, 139.0, 145.8, 157.8, 197.0. IR (neat) 3169, 1506 cm⁻¹. HRMS calcd for C₁₂H₁₃N₂S₂⁺ [M+H]⁺ 249.0515, found 249.0506. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)naphthalene-1-carbothioamide (8p).

N-(Thiophen-2-ylmethyl)-1-naphthamide (7p) (273 mg, 1.0 mmol, 1.0 equiv), Lawesson’s reagent (510 mg, 1.4 mmol, 1.3 equiv), and toluene (5.0 mL, 0.2 M) were allowed to reflux for 2 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 25% EtOAc in hexanes) to afford 8p as a yellow solid (227.2 mg, 0.80 mmol, 78%). R_f = 0.58 (25% EtOAc, in hexanes); mp 143.7–150.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.28 (d, J = 5.2 Hz, 2H), 7.00 (dd, J = 3.5, 5.1 Hz, 1H), 7.14 (dd, J = 1.1, 3.5 Hz, 1H), 7.30 (dd, J = 1.3, 5.2 Hz, 1H), 7.40–7.48 (m, 1H), 7.50 (ddd, J = 1.7, 4.5, 6.9 Hz, 2H), 7.54 (dd, J = 1.3, 7.1 Hz, 1H), 7.70 (s, 1H), 7.85 (dt, J = 1.7, 9.3 Hz, 2H), 8.10–8.17 (m, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 45.0, 124.7, 124.9, 125.2, 126.3, 126.5, 127.2, 127.3, 127.7, 128.5, 129.1, 129.9, 133.8, 137.9, 141.4, 200.2. IR (solid) 3139, 1546 cm⁻¹. HRMS calcd for C₁₆H₁₄NS₂⁺ [M+H]⁺ 284.0562, found 284.0552. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)naphthalene-2-carbothioamide (8q).

N-(Thiophen-2-ylmethyl)-2-naphthamide (7q) (123 mg, 0.46 mmol, 1.0 equiv), Lawesson’s reagent (214 mg, 0.57 mmol, 1.2 equiv) and toluene (2.3 mL, 0.2 M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 30% EtOAc in hexanes) to afford 8q as a yellow solid (113.6 mg, 0.40 mmol, 87%). R_f = 0.48 (25% EtOAc, in hexanes); mp 159.4–165.3 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.24 (dd, J = 0.9, 5.1 Hz, 2H), 7.04 (dd, J = 3.5, 5.1 Hz, 1H), 7.17 (ddd, J = 0.9, 1.6, 3.4 Hz, 1H), 7.33 (dd, J = 1.2, 5.1 Hz, 1H), 7.48–7.60 (complex, 2H), 7.81–7.86 (complex, 3H), 7.86–7.94 (complex, 2H), 8.20 (d, J = 1.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 45.7, 124.5, 126.3, 126.3, 127.1, 127.4, 127.7, 127.8, 127.9, 128.6, 129.2, 132.7, 134.7, 138.3, 138.6, 198.8. IR (solid) 3302, 1513 cm⁻¹. HRMS calcd for C₁₆H₁₄NS₂⁺ [M+H]⁺ 284.0562, found 284.0552. Purity (HPLC) >99%.

N-(Thiophen-2-ylmethyl)quinoline-2-carbothioamide (8r).

N-(Thiophen-2-ylmethyl)quinoline-2-carboxamide (7r) (184 mg, 0.68 mmol, 1.0 equiv), Lawesson’s reagent (204 mg, 0.82 mmol, 1.2 equiv) and toluene (3.4 mL, 0.2M) were allowed to reflux for 1 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 25% EtOAc in hexanes) to afford 8r as a yellow solid (146.6 mg, 0.52 mmol, 75%). R_f = 0.57 (25% EtOAc, in hexanes); mp 121.5–124.2 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.30 (dd, J = 0.8, 5.6 Hz, 2H), 7.04 (dd, J = 3.5, 5.1 Hz, 1H), 7.16–7.24 (m, 1H), 7.31 (dd, J = 1.2, 5.1 Hz, 1H), 7.62 (ddd, J = 1.2, 6.9, 8.2 Hz, 1H), 7.75 (ddd, J = 1.5, 6.9, 8.5 Hz, 1H), 7.88 (dd, J = 1.3, 8.0 Hz, 1H), 8.09 (dq, J = 1.0, 8.5 Hz, 1H), 8.29 (dd, J = 0.9, 8.7 Hz, 1H), 8.86 (d, J = 8.6 Hz, 1H), 10.59 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 44.6, 121.7, 126.0, 127.2, 127.4, 127.8, 128.3, 129.4, 129.9, 130.6, 137.3, 138.6, 145.4, 150.0, 191.0. IR (solid) 3282, 1590 cm⁻¹. HRMS calcd for C₁₅H₁₃N₂S₂⁺ [M+H]⁺ 285.0515, found 285.0508. Purity (HPLC) = 99%.

3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(Thiophen-2-ylmethyl)propanethioamide (8s).

3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(Thiophen-2-ylmethyl)propanamide (7s) (189 mg, 0.58 mmol, 1.0 equiv), Lawesson’s reagent (257 mg, 0.69 mmol, 1.2 equiv), and toluene (2.9 mL, 0.2 M) were allowed to reflux for 4 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 50% EtOAc in hexanes) to afford 8s as a white solid (176.4 mg, 0.51 mmol, 89%). R_f = 0.57 (25% EtOAc, in hexanes); mp 90.6–93.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.43 (q, J = 1.9 Hz, 3H), 2.90 (t, J = 7.5 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H), 4.91 (d, J = 4.8 Hz, 2H), 6.94 (dd, J = 1.3, 3.5 Hz, 1H), 6.96 (dd, J = 3.5, 5.0 Hz, 1H), 7.10 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.22–7.26 (complex, 2H), 7.42 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 21.6 (q, J = 2.09 Hz), 37.4, 47.3, 51.1, 127.2 (q, J = 273.5 Hz), 128.3 (q, J = 5.5 Hz), 128.7, 129.7, 130.1, 131.6 (q, J = 29.6 Hz), 134.4, 134.8, 137.4, 140.3, 140.5, 206.0; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 3186, 1549 cm⁻¹. HRMS calcd for C₁₆H₁₇F₃NOS₂⁺ [M+H]⁺ 344.0749, found 344.0744. Purity (HPLC) >99%.

3-Phenyl-N-(thiophen-2-ylmethyl)propanethioamide (8t).

3-Phenyl-N-(thiophen-2-ylmethyl)propanamide (7t) (238 mg, 0.97 mmol, 1.0 equiv), Lawesson’s reagent (514 mg, 1.3 mmol, 1.3 equiv), and toluene (4.8 mL, 0.2 M) were allowed to reflux for 2 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 30% EtOAc in hexanes) to afford 8t as a white solid (235.8 mg, 0.90 mmol, 93%). R_f= 0.45 (25% EtOAc in hexanes); mp 86.3–92.6 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.85 (dd, J = 6.4, 9.1 Hz, 2H), 2.99 (dd, J = 6.3, 9.3 Hz, 2H), 4.92 (d, J = 5.5 Hz, 2H), 6.97 (ddd, J = 2.6, 3.9, 8.5 Hz, 2H), 7.13–7.30 (m, 5H), 7.41 (dt, J = 1.6, 5.2 Hz, 1H), 10.45 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 34.9, 43.2, 46.3, 125.7, 126.0, 126.6, 126.8, 128.3, 128.3, 139.2, 140.6, 203.0. IR (solid) 3170, 1547 cm⁻¹. HRMS calcd for C₁₄H₁₆NS₂⁺ [M+H]⁺ 262.0719, found 262.0710. Purity (HPLC) >99%.

(E)-N-(Furan-2-ylmethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)prop-2-enethioamide (8u).

(E)-N-(Furan-2-ylmethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)acrylamide (7u) (115 mg, 0.37 mmol, 1.0 equiv), Lawesson’s reagent (165 mg, 0.44 mmol, 1.2 equiv), and toluene (2.5 mL, 0.2 M) were allowed to reflux for 4.5 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 100% EtOAc in hexanes) to afford 8u as a yellow oil (40.7 mg, 0.12 mmol, 34%). R_f = 0.55 (25% EtOAc, in hexanes). ¹H NMR (400 MHz, chloroform-d) δ 2.49 (q, J = 1.8 Hz, 3H), 4.98 (d, J = 4.9 Hz, 2H), 6.35–6.42 (complex, 2H), 6.83 (d, J = 15.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.39–7.46 (complex, 2H), 7.55 (dd, J = 1.7, 8.2 Hz, 1H), 7.76 (s, 1H), 7.80 (d, J = 15.3 Hz, 1H); ¹³C NMR (126 MHz, chloroform-d) δ 19.5 (q, J = 2.1 Hz), 43.1, 109.4, 110.9, 124.3 (q, J = 274.6 Hz), 125.1 (q, J = 5.6 Hz), 127.8, 129.7 (q, J = 30.1 Hz), 131.1, 132.7, 132.8, 138.6 (d, J = 2.0 Hz), 140.7, 143.0, 149.2, 194.3; ¹⁹F NMR (376 MHz, chloroform-d) δ −62.0. IR (neat) 3230, 1636 cm⁻¹. HRMS calcd for C₁₆H₁₅F₃NOS⁺ [M+H]⁺ 326.0821, found 326.0818. Purity (HPLC) = 98%.

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiophen-2-ylmethyl)prop-2-enethioamide (8v).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiophen-2-ylmethyl)acrylamide (7v) (108 mg, 0.33 mmol, 1.0 equiv), Lawesson’s reagent (142 mg, 0.38 mmol, 1.2 equiv), and toluene (2.0 mL, 0.2 M) were allowed to reflux for 3 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 60% EtOAc in hexanes) to afford 8v as a yellow amorphous solid (76.2 mg, 0.33 mmol, 67%). R_f = 0.57 (25% EtOAc, in hexanes). ¹H NMR (400 MHz, chloroform-d) δ 2.49 (d, J = 1.9 Hz, 3H), 5.15 (dd, J = 0.8, 5.1 Hz, 2H), 6.81 (d, J = 15.3 Hz, 1H), 7.01 (dd, J = 3.5, 5.1 Hz, 1H), 7.09–7.15 (m, 1H), 7.27–7.33 (m, 2H), 7.39 (d, J = 7.0 Hz, 1H), 7.55 (dd, J = 1.7, 8.1 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.81 (d, J = 15.3 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.5 (d, J = 2.0 Hz), 44.8, 124.31 (d, J = 275.3 Hz), 125.2 (q, J = 5.8 Hz), 126.3, 127.3, 127.8, 127.9, 129.7 (q, J = 29.9 Hz), 131.1, 132.8, 132.9, 138.1, 138.6, 140.8, 194.0; ¹⁹F NMR (376 MHz, chloroform-d) δ −62.0. IR (solid) 3308, 1629 cm⁻¹. HRMS calcd for C₁₆H₁₅F₃NS₂⁺ [M+H]⁺ 342.0593, found 342.0589. Purity (HPLC) >99%.

(E)-3-(4-methyl-3-(trifluoromethyl)phenyl)-N-(thiazol-2-ylmethyl)prop-2-enethioamide (8w).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiazol-2-ylmethyl)acrylamide (7w) (120 mg, 0.37 mmol, 1.0 equiv), Lawesson’s reagent (179 mg, 0.48 mmol, 1.3 equiv), and toluene (1.8 mL, 0.2 M) were allowed to reflux for 3 h. Upon cooling, the reaction was filtered over aluminum oxide and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 8w as a yellow oil (60.7 mg, 0.18 mmol, 48%). ¹H NMR (400 MHz, chloroform-d) δ 2.49 (d, J = 2.3 Hz, 3H), 5.33 (d, J = 5.0 Hz, 2H), 6.91 (d, J = 15.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 3.3 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.74–7.79 (complex, 2H), 7.82 (d, J = 15.4 Hz, 1H), 8.57 (s, 1H); ¹⁹F NMR (376 MHz, chloroform-d) δ −62.0. Due to low stability, the oil was used in the next step without further characterization.

Synthesis of building blocks 10a-10f

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)acrylic acid (10a).

4-Bromo-1-methyl-2-(trifluoromethyl)benzene (2.0 g, 8.6 mmol, 1.0 equiv), acrylic acid (890 μL, 930 mg, 13 mmol, 1.5 equiv), CsCO₃ (3.3 g, 10 mmol, 1.2 equiv), tri-o-tolylphosphane (260 mg, 0.85 mmol, 0.1 equiv), Pd(OAc)₂ (94 mg, 0.42 mmol, 0.05 equiv) and N,N-dimethylacetamide (21 mL, 0.4 M) were combined under anhydrous conditions and heated to 120 °C for 17 h. The reaction was cooled, filtered over Celite, and concentrated. The residue was treated with sodium bicarbonate and extracted three times with EtOAc. The aqueous layer was acidified to pH 1 with 1 M HCl to form a white precipitate, which was isolated via vacuum filtration to give 10a as a white powder (1.9 g, 8.3 mmol, 95%). R_f = 0.53 (94:1:5 DCM:MeOH:HOAc); mp 176.1–179.2 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.46 (q, J = 2.0 Hz, 3H), 6.63 (d, J = 16.1 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 16.0 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.95 (s, 1H), 12.46 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 18.8 (d, J = 2.2 Hz), 120.4, 124.3 (q, J = 273.7 Hz), 125.7 (q, J = 5.5 Hz), 128.0 (q, J = 29.4 Hz), 131.4, 132.6, 132.9, 138.0, 142.3, 167.4; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.9. IR (solid) 1682, 1626 cm⁻¹. HRMS calcd for C₁₁H₈F₃O₂⁻ [M-H]⁻ 229.0482, found 229.0479. Purity (HPLC) >99%.

4-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxobutanoic acid (10b).

To an oven dried flask was added Mg (51 mg, 2.09 mmol, 1.0 equiv) and THF (0.55 mL, 3.8 M). A solution of 4-bromo-1-methyl-2-(trifluoromethyl)benzene (291 μL, 500 mg, 2.09 mmol, 1.0 equiv) in THF (2.25 mL, 0.93 M) was added dropwise to the magnesium mixture over 2 min. The solution stirred overnight at room temperature. After 17.5 h, the Grignard Reagent was added dropwise to a solution of succinic anhydride (314 mg, 3.14 mmol, 1.5 equiv) in THF (0.72 M) at 0°C. The reaction was slowly warmed to room temperature and stirred for 2 h. The reaction was treated with sodium bicarbonate and extracted three times with DCM. The aqueous layer was acidified to pH2 with 1M HCl. The aqueous layer was extracted three times with EtOAc. The combined organic layers were purified via reverse phase chromatography (100% 0.1% formic acid to 100% MeOH) followed by flash chromatography (100% hexanes to 100% EtOAc) to afford 10b as a white solid (41 mg, 0.16 mmol, 8%). R_f = 0.51 (94:1:5 DCM:MeOH:HOAc); mp 139.4–146.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.55 (d, J = 1.8 Hz, 3H), 2.82 (t, J = 6.5 Hz, 2H), 3.30 (t, J = 6.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 8.02 (dd, J = 1.9, 8.0 Hz, 1H), 8.21 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.7 (q, J = 2.4 Hz), 28.0, 33.2, 124.1 (q, J = 273.9 Hz), 125.7 (q, J = 5.6 Hz), 129.57 (q, J = 30.4 Hz), 131.2, 132.6, 134.3, 142.7, 178.6, 196.5; ¹⁹F NMR (376 MHz, chloroform-d) δ −62.0. IR (solid) 2916, 1696 cm⁻¹. HMRS calcd for C₁₂H₁₀F₃O₃⁻ [M-H]⁻ 259.0588, found 259.0586. Purity (HPLC) = 92%.

(E)-3-(2-(Trifluoromethyl)phenyl)acrylic acid (10c).

2-(Trifluoromethyl)benzaldehyde (543 mg, 3.1 mmol, 1.0 equiv), 3-aminopropanoic acid (278 mg, 3.1 mmol, 1.0 equiv), and malonic acid (324 mg, 3.1 mmol, 1.0 equiv) were dissolved in pyridine (1.4 mL, 2.2 M) and refluxed for 5 h. Once cooled, the reaction was treated to pH1 with 1 M HCl to form a white precipitate which was isolated via vacuum filtration to give 10c as a white powder (451.3 g, 2.1 mmol, 67%). R_f = 0.49 (94:1:5 DCM:MeOH:HOAc); mp 228.1–235.6 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 6.63 (d, J = 15.7 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.78–7.87 (complex, 2H), 8.04 (d, J = 7.8 Hz, 1H), 12.75 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 124.1 (q, J = 273.8 Hz), 124.3, 126.1 (q, J = 5.7 Hz), 126.9 (q, J = 29.6 Hz), 128.4, 130.2, 132.5, 133.1, 137.8, 167.0; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −58.1. IR (solid) 2830, 1688 cm⁻¹. HRMS calcd for C₁₀H₆F₃O₂⁻ [M-H]⁻ 215.0325, found 215.0321. Purity (HPLC) >99%.

(E)-3-(2,4-Dichlorophenyl)acrylic acid (10d).

2,4-Dichlorobenzaldehyde (444 mg, 2.5 mmol, 1.0 equiv), 3-aminopropanoic acid (45 mg, 0.51 mmol, 0.2 equiv), and malonic acid (661 mg, 6.3 mmol, 2.5 equiv) were dissolved in pyridine (1.2 mL, 2.2 M) and refluxed for 2 h. Once cooled, the reaction was treated to pH1 with 1 M HCl to form a precipitate which was isolated via vacuum filtration to give 10d as a white powder (506.1 g, 2.3 mmol, 92%). R_f = 0.49 (94:1:5 DCM:MeOH:HOAc); mp 244.8–248.8 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 6.64 (d, J = 15.9 Hz, 1H), 7.48 (dd, J = 2.2, 8.5 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 15.9 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 12.71 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 123.0, 128.0, 129.4, 129.5, 130.9, 134.4, 135.3, 137.5, 167.0. IR (solid) 2823, 1681 cm⁻¹. HRMS calcd for C₉H₅Cl₂O₂⁻ [M-H]⁻ 214.9672, found 214.9668. Purity (HPLC) >99%.

(E)-3-(3,4-Dichlorophenyl)acrylic acid (10e).

3,4-Dichlorobenzaldehyde (230 mg, 1.3 mmol, 1.0 equiv), 3-aminopropanoic acid (116 mg, 1.3 mmol, 1.0 equiv), and malonic acid (137 mg, 1.3 mmol, 1.0 equiv) were dissolved in pyridine (0.60 mL, 2.2 M) and refluxed for 3 h. Once cooled, the reaction was treated to pH 1 with 1 M HCl to form a white precipitate which was isolated via vacuum filtration to give 10e as a white powder (215.9 g, 0.99 mmol, 76%). R_f= 0.48 (94:1:5 DCM:MeOH:HOAc); mp 258.8–265.5 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 6.64 (d, J = 16.1 Hz, 1H), 7.56 (d, J = 16.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 8.02 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 121.6, 128.2, 130.0, 131.0, 131.8, 132.4, 135.2, 141.3, 167.3. IR (solid) 2842, 1682 cm⁻¹. HRMS calcd for C₉H₅Cl₂O₂⁻ [M-H]⁻ 214.9672, found 214.9668. Purity (HPLC) = 98%.

(E)-3-(Naphthalen-1-yl)acrylic acid (10f).

1-Naphthaldehyde (113 mg, 0.72 mmol, 1.0 equiv), 3-aminopropanoic acid (116 mg, 0.73 mmol, 1.0 equiv), and malonic acid (75 mg, 0.72 mmol, 1.0 equiv) were dissolved in pyridine (0.33 mL, 2.2 M) and refluxed for 4 h. Once cooled, the reaction was treated to pH1 with 1 M HCl to form a white precipitate which was isolated via vacuum filtration to give 10f as a cream amorphous powder (111.0 g, 0.56 mmol, 77%). R_f = 0.46 (94:1:5 DCM:MeOH:HOAc). ¹H NMR (400 MHz, DMSO-d₆) δ 6.60 (d, J = 15.7 Hz, 1H), 7.52–7.68 (complex, 3H), 7.95 (d, J = 7.2 Hz, 1H), 8.01 (t, J = 8.8 Hz, 2H), 8.20 (d, J = 8.3 Hz, 1H), 8.39 (d, J = 15.7 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 121.9, 123.0, 125.2, 125.7, 126.3, 127.1, 128.7, 130.4, 130.7, 131.0, 133.3, 140.2, 167.4. IR (solid) 2825, 1674 cm⁻¹. HRMS calcd for C₁₃H₉O₂⁻ [M-H]⁻ 197.0608, found 197.0603. Purity (HPLC) >99%.

Synthesis of building blocks 11a-11f

3-(4-Methyl-3-(trifluoromethyl)phenyl)propanoic acid (11a).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)acrylic acid (10a) (242 mg, 1.0 mmol, 1.0 equiv) and Pd/C (11 mg, 0.10 mmol, 0.1 equiv) were slurried in THF (5.5 mL, 0.2 M). The suspension was sparged with H2 for 15 min. The reaction then stirred for 17 h at rt. The reaction was filtered over celite, eluted with methanol, and concentrated to give 11a as a white powder (135.4 g, 0.58 mmol, 55%). R_f = 0.49 (94:1:5 DCM:MeOH:HOAc); mp 71.2–75.1 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.39 (q, J = 2.0 Hz, 3H), 2.55 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 12.13 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.2 Hz), 30.1, 35.4, 124.6 (q, J = 273.7 Hz), 125.8 (q, J = 5.6 Hz), 129.1 (q, J = 29.6 Hz), 131.6, 132.3, 134.8 (q, J = 2.4 Hz), 137.9, 178.3; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.7. IR (solid) 2925, 1698 cm⁻¹. HRMS calcd for C₁₁H₁₀F₃O₂⁻ [M-H]⁻ 231.0638, found 231.0635. Purity (HPLC) >99%.

4-(4-Methyl-3-(trifluoromethyl)phenyl)butanoic acid (11b).

4-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxobutanoic acid (10b) (97 mg, 0.37 mmol, 1 equiv) was dissolved in HOAc (11 mL, 0.34 M). Pd/C (40 mg, 0.037 mmol, 0.1 equiv) was added and the reaction was sparged with H2 for 5 min. The reaction was then heated to 70 °C for 1h. After cooling, the reaction was filtered over a pad of Celite and purified via reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) to afford 11b as a white solid (31 mg, 0.13 mmol, 34%). R_f = 0.54 (94:1:5 DCM:MeOH:HOAc); mp 62.5–70.48 °C. ¹H NMR (400 MHz, chloroform-d) δ 1.96 (p, J = 7.5 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 2.45 (s, 3H), 2.69 (t, J = 7.7 Hz, 2H), 7.16–7.26 (complex, 2H), 7.41 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.02 (q, J = 2.2 Hz), 26.2, 33.3, 34.5, 124.7 (q, J = 273.7 Hz), 125.9 (q, J = 5.5 Hz), 129.0 (q, J = 29.7 Hz), 131.8, 132.2, 134.4 (d, J = 1.9 Hz), 139.0, 179.5; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 2942, 1689 cm⁻¹. HMRS calcd for C₁₂H₁₂F₃O₂⁻ [M-H]⁻ 245.0795, found 245.0792. Purity (HPLC) = 92%.

3-(2-(Trifluoromethyl)phenyl)propanoic acid (11c).

(E)-3-(2-(Trifluoromethyl)phenyl)acrylic acid (10c) (373 mg, 1.7 mmol, 1.0 equiv) and Pd/C (21 mg, 0.20 mmol, 0.1 equiv) were slurried in THF (8.9 mL, 0.2 M). The suspension was sparged with H₂ for 3 min. The reaction then stirred for 16 h at rt. The reaction was filtered over Celite, eluted with methanol, and concentrated to give 11c as a white powder (310.3 g, 1.4 mmol, 82%). R_f = 0.47 (94:1:5 DCM:MeOH:HOAc); mp 96.5–102.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.51–2.58 (complex, 2H), 2.95–3.03 (complex, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 12.27 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 27.0, 34.9, 124.6 (q, J = 273.8 Hz), 125.8 (q, J = 5.9 Hz), 126.8,127.0 (q, J = 29.2 Hz), 131.0, 132.6, 139.3, 173.3; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −59.1. IR (solid) 2926, 1704 cm⁻¹. HRMS calcd for C₁₀H₈F₃O₂⁻ [M-H]⁻ 217.0482, found 217.0478. Purity (HPLC) >99%.

3-(2,4-Dichlorophenyl)propanoic acid (11d).

(E)-3-(2,4-Dichlorophenyl)acrylic acid (10d) (211 mg, 0.97 mmol, 1.0 equiv) and Pd/C (12 mg, 0.11 mmol, 0.1 equiv) were slurried in THF (5.0 mL, 0.2 M). The suspension was sparged with H2 for 8 minutes. The reaction then stirred for 20 h at rt. The reaction was filtered over Celite, eluted with methanol, and concentrated. The residue was dissolved in sodium bicarbonate and extracted three times with DCM. The aqueous layer was acidified to pH1 using 1M HCl to give a precipitate which was isolated via vacuum filtration to give 11d as a white amorphous powder (68.0 mg, 0.31 mmol, 32%). R_f = 0.63 (94:1:5 DCM:MeOH:HOAc). ¹H NMR (400 MHz, chloroform-d) δ 2.69 (t, J = 7.5 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H), 7.19 (d, J = 2.6 Hz, 2H), 7.38 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 28.2, 33.6, 127.4, 129.5, 131.4, 133.1, 134.7, 136.3, 178.4. IR (solid) 2919, 1707 cm⁻¹. HRMS calcd for C₉H₇Cl₂O₂⁻ [M-H]⁻ 216.9829, found 216.9825. Purity (HPLC) = 93%.

3-(3,4-Dichlorophenyl)propanoic acid (11e).

(E)-3-(3,4-Dichlorophenyl)acrylic acid (10e) (110 mg, 0.51 mmol, 1.0 equiv) and Pd/C (5.4 mg, 0.051 mmol, 0.1 equiv) were slurried in THF (2.5 mL, 0.2 M). The suspension was sparged with H2 for 10 minutes. The reaction then stirred for 2 days at rt. The reaction was filtered over Celite, eluted with methanol, and concentrated to give 11e as a white amorphous powder (107.8 mg, 0.49 mmol, 97%). R_f = 0.40 (94:1:5 DCM:MeOH:HOAc). ¹H NMR (400 MHz, DMSO-d₆) δ 2.55 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 7.24 (dd, J = 2.0, 8.2 Hz, 1H), 7.48–7.56 (complex, 2H), 12.16 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 29.3, 34.6, 128.6, 128.8, 130.3, 130.4, 130.7, 142.2, 173.5. IR (solid) 2942, 1707 cm⁻¹. HRMS calcd for C₉H₇Cl₂O₂⁻ [M-H]⁻ 216.9829, found 216.9825. HPLC purity = 97%.

3-(Naphthalen-1-yl)propanoic acid (11f).

(E)-3-(Naphthalen-1-yl)acrylic acid (10f) (249 mg, 1.2 mmol, 1.0 equiv) and Pd/C (24 mg, 0.22 mmol, 0.2 equiv) were slurried in THF (6.0 mL, 0.2 M). The suspension was sparged with H₂ for 5 min. The reaction then stirred for 18 h at rt. The reaction was filtered over Celite, eluted with methanol, and concentrated to give 11f as a brown powder (246.2 g, 1.2 mmol, 98%). R_f = 0.50 (94:1:5 DCM:MeOH:HOAc); mp 187.9–193.5 °C. ¹H NMR (400 MHz, methanol-d₄) δ 2.69–2.75 (complex, 2H), 3.36–3.43 (complex, 2H), 7.34–7.42 (complex, 2H), 7.47 (ddd, J = 1.3, 6.8, 8.0 Hz, 1H), 7.53 (ddd, J = 1.5, 6.8, 8.5 Hz, 1H), 7.72 (dt, J = 3.5, 6.9 Hz, 1H), 7.83–7.88 (m, 1H), 8.07 (dq, J = 0.9, 8.6 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 27.4, 34.6, 123.4, 125.6, 125.6, 125.7, 126.2, 126.7, 128.7, 131.2, 133.4, 136.8, 173.8. IR (solid) 2922, 1697 cm⁻¹. HRMS calcd for C₁₃H₁₂O₂⁻ [M-H]⁻ 199.0765, found 199.0759. Purity (HPLC) >99%.

Synthesis of hydrazides 9a-9p

2-(4-Methyl-3-(trifluoromethyl)phenyl)acetohydrazide (9a).

2-(4-Methyl-3-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.3 mmol, 1.0 equiv) and sulfuric acid (12.3 μL, 23 mg, 0.23 mmol, 0.1 equiv) were refluxed in MeOH (1.15 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (445 μL, 459 mg, 9.2 mmol, 4.0 equiv) was added. The reaction refluxed for 2 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9a as a white crystalline solid (269.2 mg, 1.2 mmol, 51%). R_f = 0.42 (100% EtOAc); mp 154.0–158.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.47 (q, J = 1.8 Hz, 3H), 3.54 (s, 2H), 3.74–4.03 (complex, 2H), 6.84 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (q, J = 2.1 Hz), 41.2, 124.4 (q, J = 273.7 Hz), 126.7 (q, J = 5.5 Hz), 129.6 (q, J = 29.9 Hz), 131.9, 132.6, 132.7, 136.1, 171.2; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.81. IR (solid) 3286, 1672 cm⁻¹. HRMS calcd for C₁₀H₁₂F₃N₂O⁺ [M+H]⁺ 233.0896, found 233.0894. Purity (HPLC) >99%.

3-(4-Methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b).

3-(4-Methyl-3-(trifluoromethyl)phenyl)propanoic acid (11a) (454 mg, 2.0 mmol, 1.0 equiv) and sulfuric acid (10.5 μL, 19 mg, 0.20 mmol, 0.1 equiv) were refluxed in MeOH (0.980 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (380 μL, 392 mg, 7.8 mmol, 4.0 equiv) was added. The reaction refluxed for 3 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9b as a white crystalline solid (305.9 mg, 1.2 mmol, 63%). R_f = 0.35 (100% EtOAc); mp 134.2–139.6°C. ¹H NMR (400 MHz, chloroform-d) δ 2.40–2.48 (complex, 5H), 2.98 (t, J = 7.6 Hz, 2H), 3.86 (s, 2H), 6.74 (s, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (d, J = 2.4 Hz), 30.9, 36.1, 124.6 (q, J = 273.7 Hz), 125.7 (q, J = 5.5 Hz), 129.2 (q, J = 29.6 Hz), 131.7, 132.3, 134.8, 138.3, 172.6; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.7. IR (solid) 3285, 1631 cm⁻¹. HRMS calcd for C₁₁H₁₄N₂O⁺ [M+H]⁺ 247.1053, found 247.1050. Purity (HPLC) >99%.

4-(4-Methyl-3-(trifluoromethyl)phenyl)butanehydrazide (9c).

4-(4-Methyl-3-(trifluoromethyl)phenyl)butanoic acid (11b) (48 mg, 0.19 mmol, 1.0 equiv) and sulfuric acid (1.04 μL, 1.9 mg, 0.0019 mmol, 0.1 equiv) were refluxed in MeOH (0.5 mL, 0.4 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (445 μL, 459 mg, 9.2 mmol, 4.0 equiv) was added. The reaction refluxed for 2 h. The solvent was removed and the oil was purified via reverse phase chromatography (100% water to 100% MeOH) to give 9c as a white solid (9.2 mg, 0.035 mmol, 18%). R_f = 0.38 (5% MeOH, in DCM); mp 112.9–116.9 °C. ¹H NMR (600 MHz, chloroform-d) δ 1.97 (p, J = 7.5 Hz, 2H), 2.15 (t, J = 7.5 Hz, 2H), 2.43 (q, J = 1.9 Hz, 3H), 2.65 (t, J = 7.6 Hz, 2H), 3.89 (s, 2H), 6.82 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.2 Hz), 26.8, 33.7, 34.7, 124.7 (q, J = 273.8 Hz), 125.8 (q, J = 5.6 Hz), 129.0 (q, J = 29.4 Hz), 131.7, 132.1, 134.38 (q, J = 1.8 Hz), 139.1, 173.5; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 3298, 1654 cm⁻¹. HRMS calcd for C¹²H₁₆N₂O⁺ [M+H]⁺ 261.1209, found 261.1209. Purity (HPLC) >99%.

3-(4-Methoxyphenyl)propanehydrazide (9d).

3-(4-Methoxyphenyl)propanoic acid (492 mg, 2.7 mmol, 1.0 equiv) and sulfuric acid (14.6 μL, 27 mg, 0.27 mmol, 0.1 equiv) were refluxed in MeOH (1.4 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (530 μL, 547 mg, 10.9 mmol, 4.0 equiv) was added. The reaction refluxed for 3.5 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9d as a white solid (491.8 mg, 2.5 mmol, 93%). R_f = 0.33 (100% EtOAc); mp 153.2–163.7 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.23–2.30 (complex, 2H), 2.70–2.76 (complex, 2H), 3.71 (d, J = 2.1 Hz, 3H), 4.16 (s, 2H), 6.79–6.85 (complex, 2H), 7.05–7.13 (complex, 2H), 8.93 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 30.2, 35.4, 55.0, 113.7, 129.1, 133.1, 157.5, 170.8. IR (solid) 3310, 1628 cm⁻¹. HRMS calcd for C₁₀H₁₅N₂O₂⁺ [M+H]⁺ 195.1128, found 195.1128. Purity (HPLC) >99%.

3-(4-Fluorophenyl)propanehydrazide (9e).

3-(4-Fluorophenyl)propanoic acid (98 mg, 0.58 mmol, 1.0 equiv) and sulfuric acid (3 μL, 6 mg, 0.58 mmol, 0.1 equiv) were refluxed in MeOH (1.15 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (113 μL, 117 mg, 2.3 mmol, 4.0 equiv) was added. The reaction refluxed for 2 h. The reaction was concentrated and purified via reversed phase chromatography (100% water to 100% acetonitrile) to afford 9e as a white solid (56.4 mg, 0.31 mmol, 53%). R_f = 0.34 (5% MeOH in DCM); mp 256.6–261.5 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.30 (dd, J = 6.9, 8.5 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H), 4.15 (s, 2H), 7.02–7.13 (complex, 2H), 7.17–7.27 (complex, 2H), 8.94 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 29.8, 32.7, 114.9 (d, J = 20.9 Hz), 130.0 (d, J = 8.0 Hz), 137.1 (d, J = 3.1 Hz), 160.7 (d, J = 241.2 Hz), 170.0; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −118.0. IR (solid) 3203, 1588 cm⁻¹. HRMS calcd for C₉H₁₂FN₂O⁺ [M+H]⁺ 183.0928, found 183.0923. Purity (HPLC) = 97%.

3-(4-Chlorophenyl)propanehydrazide (9f).

3-(4-Chlorophenyl)propanoic acid (503 mg, 2.7 mmol, 1.0 equiv) and CDI (586 mg, 3.6 mmol, 1.3 equiv) were dissolved in THF (2.0 mL, 1.0 M) for 2 min. The reaction was then cooled to 0 °C and hydrazine monohydrate (1.3 mL, 1.4 mg, 0.27 mmol, 10 equiv) was added. The reaction was refluxed for 5 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9f as a white crystalline solid (438.5 mg, 2.2 mmol, 81%). R_f = 0.37 (100% EtOAc); mp 120.3–124.1 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.26–2.35 (complex, 2H), 2.80 (t, J = 7.7 Hz, 2H), 4.19 (s, 2H), 7.17–7.24 (complex, 2H), 7.28–7.34 (complex, 2H), 8.96 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 30.3, 34.8, 128.2, 130.1, 130.5, 140.2, 170.6. IR (solid) 3317, 1629 cm⁻¹. HRMS calcd for C₉H₁₂ClN₂O⁺ [M+H]⁺ 199.0633, found 199.0638. Purity (HPLC) >99%.

3-(4-Bromophenyl)propanehydrazide (9g).

3-(4-Bromophenyl)propanoic acid (506 mg, 2.2 mmol, 1.0 equiv) and sulfuric acid (11.8 μL, 22 mg, 0.22 mmol, 0.1 equiv) were refluxed in MeOH (1.15 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (429 μL, 442 mg, 8.8 mmol, 4.0 equiv) was added. The reaction refluxed for 4 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9g as a white crystalline solid (372.7 mg, 2.2 mmol, 69%). R_f = 0.39 (100% EtOAc); mp 138.7–141.3 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.30 (dd, J = 7.0, 8.4 Hz, 2H), 2.78 (t, J = 7.7 Hz, 2H), 4.15 (s, 2H), 7.12–7.18 (complex, 2H), 7.40–7.48 (complex, 2H), 8.95 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 30.3, 34.7, 118.9, 130.6, 131.1, 140.7, 170.5. IR (solid) 3281, 1624 cm⁻¹. HRMS calcd for C₉H₁₂BrN₂O⁺ [M+H]⁺ 243.0128, found 243.0126. Purity (HPLC) >99%.

3-(3-Bromophenyl)propanehydrazide (9h).

3-(3-Bromophenyl)propanoic acid (382 mg, 1.7 mmol, 1.0 equiv) and sulfuric acid (8.9 μL, 16 mg, 0.17 mmol, 0.1 equiv) were refluxed in MeOH (0.83 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (324 μL, 334 mg, 6.7 mmol, 4.0 equiv) was added. The reaction refluxed for 2 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9h as an off-white solid (285.1 mg, 1.2 mmol, 70%). R_f = 0.46 (100% EtOAc); mp 124.3–130.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.39–2.47 (complex, 2H), 2.95 (t, J = 7.6 Hz, 2H), 3.86 (s, 2H), 6.62 (s, 1H), 7.10–7.19 (complex, 2H), 7.30–7.37 (complex, 2H); ¹³C NMR (101 MHz, chloroform-d δ 31.1, 36.0, 122.7, 127.1, 129.7, 130.3, 131.5, 142.9, 172.7. IR (solid) 3307, 1626 cm⁻¹. HRMS calcd for C₉H₁₂BrN₂O⁺ [M+H]⁺ 243.0128, found 243.0124. Purity (HPLC) >99%.

3-(2-Bromophenyl)propanehydrazide (9i).

3-(2-Bromophenyl)propanoic acid (502 mg, 2.2 mmol, 1.0 equiv) and sulfuric acid (11.7 μL, 21 mg, 0.22 mmol, 0.1 equiv) were refluxed in MeOH (1.1 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (425 μL, 439 mg, 8.8 mmol, 4.0 equiv) was added. The reaction refluxed for 4 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9i as a white solid (483.8 mg, 2.0 mmol, 91%). R_f = 0.33 (5% MeOH, in DCM); mp 121.8–126.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.25–2.38 (complex, 2H), 2.86–2.96 (complex, 2H), 4.17 (s, 2H), 7.15 (ddd, J = 3.5, 5.6, 8.0 Hz, 1H), 7.29–7.33 (complex, 2H), 7.55–7.59 (m, 1H), 8.99 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 31.3, 33.2, 123.7, 127.9, 128.3, 130.4, 132.5, 140.1, 170.3. IR (solid) 3307, 1634 cm⁻¹. HRMS calcd for C₉H₁₂BrN₂O⁺ [M+H]⁺ 243.0128, found 243.0127. Purity (HPLC) >99%.

3-(2-(Trifluoromethyl)phenyl)propanehydrazide (9j).

3-(2-(Trifluoromethyl)phenyl)propanoic acid (11c) (504 mg, 2.3 mmol, 1.0 equiv) and sulfuric acid (12.4 μL, 23 mg, 0.23 mmol, 0.1 equiv) were refluxed in MeOH (1.2 mL, 2.0 M) for 3 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (449 μL, 463 mg, 9.2 mmol, 4.0 equiv) was added. The reaction refluxed for 3 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9j as a white solid (451.6 mg, 1.9 mmol, 84%). R_f = 0.50 (100% EtOAc); mp 91.7–99.0 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.27–2.37 (complex, 2H), 2.98 (t, J = 8.0 Hz, 2H), 4.18 (d, J = 4.1 Hz, 2H), 7.37–7.50 (complex, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 9.01 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 28.5, 36.3, 124.7 (q, J = 273.7 Hz), 126.3 (q, J = 5.6 Hz), 126.7, 128.55 (q, J = 29.8 Hz), 131.3, 132.2, 139.3, 172.7; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.0. IR (solid) 3310, 1628 cm⁻¹. HRMS calcd for C₁₀H₁₂F₃N₂O⁺ [M+H]⁺ 233.0896, found 233.0895. Purity (HPLC) >99%.

3-(2,4-Dichlorophenyl)propanehydrazide (9k).

3-(2,4-Dichlorophenyl)propanoic acid (11d) (198 mg, 0.90 mmol, 1.0 equiv) and sulfuric acid (4.8 μL, 8.9 mg, 0.090 mmol, 0.1 equiv) were refluxed in MeOH (904 μL, 1.0 M) for 2 hours. The reaction was then cooled to 0 °C and hydrazine mononhydrate (175 μL, 181 mg, 3.6 mmol, 4.0 equiv) was added. The reaction refluxed for 2 hours. Upon cooling, a white solid was precipitated out using water. The solid was collected via vacuum filtration to give 9k as a brown solid (62.1 mg, 0.27 mmol, 30%). R_f = 0.44 (100% EtOAc); mp 147.9–154.1 °C. ¹H NMR (400 MHz, DMSO-d⁶) δ 2.32 (t, J = 7.9 Hz, 2H), 2.90 (t, J = 7.7 Hz, 3=2H), 4.30 (s, 2H), 7.30–7.39 (complex, 3H), 7.56 (d, J = 2.0 Hz, 1H), 8.99 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 28.2, 32.8, 127.3, 128.6, 131.5, 131.8, 133.8, 137.6, 170.1. IR (solid) 3324, 1626 cm⁻¹. HRMS calcd for C₉H₁₁Cl₂N₂O⁺ [M+H]⁺ 233.0243, found 233.0242. Purity (HPLC) = 95%.

3-(3,4-Dichlorophenyl)propanehydrazide (9l).

3-(3,4-Dichlorophenyl)propanoic acid (11e) (137 mg, 0.62 mmol, 1.0 equiv) and sulfuric acid (3.35 μL, 6.1 mg, 0.062 mmol, 0.1 equiv) were refluxed in MeOH (626 μL, 1.0 M) for 2.5 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (429 μL, 442 mg, 8.8 mmol, 4.0 equiv) was added. The reaction refluxed for 2.5 h. Upon cooling, a white solid precipitated out upon the addition of water. The solid was collected via vacuum filtration to give 9l as a white crystalline solid (127.5 mg, 0.55 mmol, 87%). R_f = 0.35 (100% EtOAc); mp 121.6–126.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.33 (t, J = 7.6 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 4.15 (s, 2H), 7.19 (dd, J = 2.1, 8.3 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 8.94 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 30.7, 35.3, 129.6, 129.7, 131.1, 131.3, 131.7, 142.9, 172.3. IR (solid) 3303, 1627 cm⁻¹. HRMS calcd for C₉H₁₁Cl₂N₂O⁺ [M+H]⁺ 233.0243, found 233.0242. Purity (HPLC) >99%.

3-(Naphthalen-1-yl)propanehydrazide (9m).

3-(Naphthalen-1-yl)propanoic acid (11f) (229 mg, 1.1 mmol, 1.0 equiv) and sulfuric acid (6.1 μL, 11 mg, 0.11 mmol, 0.1 equiv) were refluxed in MeOH (0.57 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (222 μL, 229 mg, 4.6 mmol, 4.0 equiv) was added. The reaction refluxed for 3.5 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9m as an off-white solid (170.0 mg, 0.79 mmol, 69%). R_f = 0.40 (100% EtOAc); mp 151.9–159.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.39–2.48 (complex, 2H), 3.25–3.31 (complex, 2H), 4.18 (s, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.40–7.44 (m, 1H), 7.49–7.59 (complex, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 9.01 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 28.1, 34.5, 123.5, 125.6, 125.6, 125.7, 126.0, 126.58, 128.61, 131.2, 133.4, 137.2, 170.8. IR (solid) 3314, 1630 cm⁻¹. HRMS calcd for C₁₃H₁₅N₂O⁺ [M+H]⁺ 215.1179, found 215.1178. Purity (HPLC) >99%.

3-(Naphthalen-2-yl)propanehydrazide (9n).

3-(Naphthalen-2-yl)propanoic acid (495 mg, 2.5 mmol, 1.0 equiv) and sulfuric acid (13.2 μL, 24 mg, 0.25 mmol, 0.1 equiv) were refluxed in MeOH (1.2 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (479 μL, 495 mg, 9.9 mmol, 4.0 equiv) was added. The reaction refluxed for 2 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9n as a white solid (493.7 mg, 2.3 mmol, 93%). R_f = 0.30 (5% MeOH, in DCM); mp 186.3–195.0 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.48–2.58 (complex, 2H), 3.14 (t, J = 7.6 Hz, 2H), 3.85 (s, 2H), 6.65 (s, 1H), 7.32 (dd, J = 1.8, 8.4 Hz, 1H), 7.41–7.49 (complex, 2H), 7.63 (s, 1H), 7.75–7.83 (complex, 3H); ¹³C NMR (101 MHz, chloroform-d) δ 31.7, 36.4, 125.6, 126.3, 126.7, 127.0, 127.6, 127.8, 128.4, 132.3, 133.7, 138.1, 173.0. IR (solid) 3278, 1625 cm⁻¹. HRMS calcd for C₁₃H₁₅N₂O⁺ [M+H]⁺ 215.1179, found 215.1175. Purity (HPLC) >99%.

1,2,3,4-Tetrahydronaphthalene-2-carbohydrazide (9o).

1,2,3,4-Tetrahydronaphthalene-2-carboxylic acid (251 mg, 1.4 mmol, 1.0 equiv) and sulfuric acid (7.6 μL, 14 mg, 0.14 mmol, 0.1 equiv) were refluxed in MeOH (713 μL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (277 μL, 286 mg, 5.7 mmol, 4.0 equiv) was added. The reaction refluxed for 3.5 h. Upon cooling, the reaction was purified via flash chromatography (100% hexanes to 100% EtOAc followed by 100% DCM to 0.8% MeOH, in DCM) to give 9o as a white solid (52.5 mg, 0.28 mmol, 19%). R_f = 0.40 (100% EtOAc); mp 137.0–144.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 1.70 (qd, J = 5.9, 12.3 Hz, 1H), 1.90 (d, J = 13.5 Hz, 1H), 2.44 (dt, J = 8.6, 14.7 Hz, 1H), 2.78 (complex, 4H), 4.21 (s, 2H), 7.06 (s, 4H), 9.05 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 26.2, 28.1, 31.8, 38.7, 125.5, 125.6, 128.6, 128.8, 135.4, 135.5, 174.1. IR (solid) 3295, 1623 cm⁻¹. HRMS calcd for C₁₁H₁₅N₂O⁺ [M+H]⁺ 191.1179, found 191.1178. Purity (HPLC) = 99%.

3-Hydroxy-3-phenylpropanehydrazide (9p).

3-Hydroxy-3-phenylpropanoic acid (487 mg, 2.9 mmol, 1.0 equiv) and sulfuric acid (15.7 μL, 29 mg, 0.29 mmol, 0.1 equiv) were refluxed in MeOH (1.5 mL, 2.0 M) for 2 h. The reaction was then cooled to 0 °C and hydrazine monohydrate (569 μL, 587 mg, 11.7 mmol, 4.0 equiv) was added. The reaction refluxed for 2.5 h. Upon cooling, a white solid precipitated out following the addition of water. The solid was collected via vacuum filtration to give 9p as a white solid (452.9 mg, 2.5 mmol, 86%). R_f = 0.23 (5% MeOH, in DCM); mp 202.4–210.8 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.18–2.40 (m, 2H), 4.13 (s, 2H), 4.93 (dt, J = 4.7, 9.0 Hz, 1H), 5.32 (dd, J = 0.6, 4.5 Hz, 1H), 7.12–7.39 (complex, 4H), 8.92 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 43.9, 69.5, 125.7, 126.8, 128.0, 145.3, 169.4. IR (solid) 3298, 1641 cm⁻¹. HRMS calcd for C₉H₁₃N₂O⁺ [M+H]⁺ 181.0972, found 181.0970. Purity (HPLC) >99%.

Synthesis of triazoles 2a-2k, 3a-3j, 4a-4l, 5a, 5d, 5h, 5j, 6a-6e

2-(4-(Furan-2-ylmethyl)-5-(4-methyl-3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-yl)pyridine (2a).

N-(Furan-2-ylmethyl)pyridine-2-carbothioamide (8a) (52 mg, 0.24 mmol, 1.0 equiv), 2-(4-methyl-3-(trifluoromethyl)phenyl)acetohydrazide (9a) (67 mg, 0.29 mmol, 1.2 equiv), AgOBz (111 mg, 0.48 mmol, 2.0 equiv), and HOAc (41 μL, 43 mg, 0.72 mmol, 3.0 equiv) in DCM (1.2 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.2 mL, 0.2 M). The suspension was treated with 1M HCl (0.48 mL, 17 mg, 0.48 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (83 μL, 62 mg, 0.48 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reversed phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2a as a clear, colorless oil (48.0 mg, 0.12 mmol, 50%). R_f = 0.69 (5% MeOH in DCM). ¹H NMR (400 MHz, DMSO-d₆) δ 2.37 (q, J = 1.9 Hz, 3H), 4.32 (s, 2H), 5.88 (s, 2H), 6.09 (dd, J = 0.8, 3.3 Hz, 1H), 6.21 (dd, J = 1.9, 3.2 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.37–7.42 (complex, 2H), 7.47 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.52 (s, 1H), 7.94 (td, J = 1.8, 7.8 Hz, 1H), 8.08 (dt, J = 1.1, 8.0 Hz, 1H), 8.68 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.3 Hz), 31.0, 41.5, 109.0, 110.7, 123.9, 124.2, 124.5 (d, J = 273.7 Hz), 126.1 (d, J = 5.6 Hz), 129.4 (d, J = 30.1 Hz), 132.0, 132.6, 133.3, 135.8, 137.2, 142.8, 148.2, 148.6, 149.2, 152.2, 155.0; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.3. IR (solid) 1590, 1504 cm⁻¹. HRMS calcd for C₂₁H₁₈F₃N₄O⁺ [M+H]⁺ 399.1427, found 399.1434. Purity (HPLC) = 98%.

2-(4-(Furan-2-ylmethyl)-5-(4-methyl-3-(trifluoromethyl)phenethyl)-4H-1,2,4-triazol-3-yl)pyridine (2b).

N-(Furan-2-ylmethyl)pyridine-2-carbothioamide (8a) (32 mg, 0.14 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (42 mg, 0.17 mmol, 1.2 equiv.), AgOBz (65 mg, 0.286 mmol, 2.0 equiv), and HOAc (24 μL, 0.43 mmol, 3.0 equiv) in DCM (0.7 mL, 0.2M) were stirred at room temperature for 15 h. The reaction was concentrated and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 2b as a clear, colorless oil (20 mg, 0.14 mmol 34%). R_f = 0.28 (100% EtOAc). ¹H NMR (401 MHz, chloroform-d) δ 2.45 (q, J = 1.9 Hz, 3H), 3.13–3.27 (m, 4H), 5.82 (s, 2H), 6.12 (dd, J = 0.9, 3.3 Hz, 1H), 6.23 (dd, J = 1.9, 3.3 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.27 (dd, J = 0.84, 1.88 Hz, 1H), 7.34 (ddd, J = 1.2, 4.8, 7.6 Hz, 2H), 7.50 (s, 1H), 7.81 (td, J = 1.8, 7.8 Hz, 1H), 8.29 (dt, J = 1.1, 8.0 Hz, 1H), 8.65 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 19.1 (q, J = 2.2 Hz), 27.0, 32.7, 41.3, 108.9, 110.7, 123.9, 124.1, 124.7 (d, J = 275.0 Hz), 125.8 (q, J = 5.4 Hz), 129.1 (d, J = 29.8 Hz), 132.3, 134.8 (d, J = 1.9 Hz), 137.2, 138.5, 142.8, 148.3, 148.6, 149.4, 151.7, 156.0; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 2923, 1590 cm⁻¹. HRMS calcd for C₂₂H₁₉F₃N₄O⁺ [M+H]⁺ 413.1584, found 413.1579. Purity (HPLC) = 98%.

2-(4-(Furan-2-ylmethyl)-5-(3-(4-methyl-3-(trifluoromethyl)phenyl)propyl)-4H-1,2,4-triazol-3-yl)pyridine (2c).

N-(Furan-2-ylmethyl)pyridine-2-carbothioamide (8a) (15 mg, 0.70 mmol, 1.0 equiv), 4-(4-methyl-3-(trifluoromethyl)phenyl)butanehydrazide (9c) (22 mg, 0.084 mmol, 1.2 equiv), AgOBz (32 mg, 0.14 mmol, 2.0 equiv), and HOAc (12 μL, 13 mg, 0.21 mmol, 3.0 equiv) in DCM (0.3 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was filtered over Celite, concentrated, and purified via reversed phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) to afford 2c as a clear, colorless oil (17.2 mg, 0.040 mmol, 57%). R_f = 0.20 (100% EtOAc). ¹H NMR (600 MHz, chloroform-d) δ 2.19 (p, J = 7.6 Hz, 2H), 2.44 (s, 3H), 2.81 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 5.82 (s, 2H), 6.07 (d, J = 3.3 Hz, 1H), 6.21 (dd, J = 1.8, 3.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.29–7.36 (m, 1H), 7.44 (s, 1H), 7.81 (td, J = 1.8, 7.8 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 4.8 Hz, 1H); ¹³C NMR (401 MHz, chloroform-d) δ 19.0 (q, J = 2.1 Hz), 24.4, 28.4, 34.7, 41.3, 108.8, 110.6, 123.8, 124.1, 124.8 (q, J = 272.8), 125.9 (q, J = 5.5 Hz), 128.9 (q, J = 29.4 Hz), 131.9, 132.1, 134.3, 137.2, 139.3, 142.7, 148.4, 148.6, 149.5, 151.7, 156.5; ¹⁹F NMR ( MHz, chloroform-d) δ −61.6. IR (neat) 2934, 1664 cm⁻¹. HRMS calcd for C₂₃H₂₂F₃N₄O⁺ [M+H]⁺ 427.1740, found 427.1743. Purity (HPLC) >99%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (2d).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (80 mg, 0.34 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (101 mg, 0.411 mmol, 1.2 equiv), AgOBz (157 mg, 0.68 mmol, 2.0 equiv), and HOAc (59 μL, 62 mg, 1.0 mmol, 3.0 equiv) in DCM (1.7 mL, 0.2 M) were stirred at room temperature for 16 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.6 mL, 0.2 M). The suspension was treated with 1M HCl (0.68 mL, 25.0 mg, 0.69 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (123 μL, 89 mg, 0.69 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reversed phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2d as a white solid (55.6 mg, 0.13 mmol, 38%). R_f= 0.30 (100% EtOAc); mp 194.4–198.0 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.45 (d, J = 2.0 Hz, 3H), 3.06–3.21 (complex, 4H), 5.96 (s, 2H), 6.84–6.87 (m, 1H), 6.88–6.91 (m, 1H), 7.17–7.22 (complex, 2H), 7.27–7.32 (m, 1H), 7.35 (ddd, J = 1.2, 4.9, 7.7 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.84 (td, J = 1.8, 7.8 Hz, 1H), 8.34 (dt, J = 1.1, 8.0 Hz, 1H), 8.65 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.0 Hz), 27.2, 32.7, 43.5, 123.8, 124.3, 124.7 (q, J = 274.0 Hz), 125.8 (q, J = 5.4 Hz), 126.4, 126.6, 126.9, 129.2 (q, J = 29.5 Hz), 131.9, 132.4, 134.9, 137.3, 138.4, 138.5, 148.1, 148.7, 151.6, 155.8; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 1590, 1503 cm⁻¹. HRMS calcd for C₂₂H₂₀F₃N₄S⁺ [M+H]⁺ 429.1355, found 429.1358. Purity (HPLC) = 98%.

2-((3-(4-Methyl-3-(trifluoromethyl)phenethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-yl)methyl)thiazole (2e).

N-(Thiazol-2-ylmethyl)pyridine-2-carbothioamide (8c) (51 mg, 0.22 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (64 mg, 0.26 mmol, 1.2 equiv), AgOBz (100 mg, 0.435 mmol, 2.0 equiv), and HOAc (37 μL, 39.2 mg, 0.63 mmol, 3.0 equiv) in DCM (1.0 mL, 0.2 M) were stirred at room temperature for 16.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.44 mL, 16 mg, 0.44 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (78 μL, 56 mg, 0.44 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 5% MeOH in DMC) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2f as a white solid (5.8 mg, 0.014 mmol, 6%). R_f = 0.48 (5% MeOH in DCM); mp 89.31–94.19 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.44 (d, J = 1.9 Hz, 3H), 3.15–3.22 (complex, 2H), 3.24–3.34 (complex, 2H), 6.09 (s, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 3.3 Hz, 1H), 7.32–7.43 (complex, 2H), 7.48 (s, 1H), 7.73 (d, J = 3.2 Hz, 1H), 7.87 (td, J = 1.8, 7.8 Hz, 1H), 8.39 (dt, J = 1.1, 8.1 Hz, 1H), 8.67 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.0 Hz), 27.0, 32.7, 46.0, 121.2, 123.7, 124.5, 125.6, 125.9 (q, J = 5.6 Hz), 129.1 (q, J = 29.6 Hz), 132.0, 132.3, 134.8, 137.5, 138.2, 142.6, 147.6, 148.6, 151.1, 156.4, 164.1; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 1590, 1504 cm⁻¹. HRMS calcd for C₂₁H₁₉F₃N₅S⁺ [M+H]⁺ 430.1308, found 430.1304. Purity (HPLC) >99%.

2-(4-Benzyl-5-(4-methyl-3-(trifluoromethyl)phenethyl)-4H-1,2,4-triazol-3-yl)pyridine (2f).

N-Benzylpyridine-2-carbothioamide (8d) (75 mg, 0.33 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (98 mg, 0.40 mmol, 1.2 equiv), AgOBz (151 mg, 0.66 mmol, 2.0 equiv), and HOAc (57 μL, 60 mg, 1.0 mmol, 3.0 equiv) in DCM (1.7 mL, 0.2 M) were stirred at room temperature for 20 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.7 mL). The suspension was treated with 1M HCl (0.66 mL, 24 mg, 0.44 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (115 μL, 85 mg, 0.66 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) followed by preparatory TLC (3% MeOH in DCM) afforded 2g as a white oil (53.0 mg, 0.12 mmol, 38%). R_f = 0.40 (100% EtOAc). ¹H NMR (400 MHz, chloroform-d) δ 2.43 (q, J = 1.9 Hz, 3H), 2.88–2.97 (complex, 2H), 2.99–3.05 (complex, 2H), 5.84 (s, 2H), 6.98–7.06 (complex, 2H), 7.12–7.21 (complex, 2H), 7.24–7.32 (complex, 4H), 7.81 (td, J = 1.8, 7.8 Hz, 1H), 8.34 (dt, J = 1.1, 8.0 Hz, 1H), 8.54 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (126 MHz, chloroform-d) δ 19.04 (q, J = 2.1 Hz), 27.2, 32.8, 48.1, 123.9, 124.1, 124.6 (q, J = 274.2 Hz), 125.8 (q, J = 5.5 Hz), 126.6, 128.0, 129.0, 129.0 (q, J = 29.7 Hz), 131.8, 132.3, 134.7 (d, J = 1.8 Hz), 136.2, 137.2, 138.3, 148.2, 148.8, 152.2, 156.3; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 2927, 1589 cm⁻¹. HRMS calcd for C₂₄H₂₂F₃N₄⁺ [M+H]⁺ 423.1791, found 423.1776. Purity (HPLC) >99%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)pyridine (2g).

N-Phenylpyridine-2-carbothioamide (8e) (57 mg, 0.26 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (78 mg, 0.32 mmol, 1.2 equiv), AgOBz (121 mg, 0.53 mmol, 2.0 equiv), and HOAc (45 μL, 48 mg, 0.80 mmol, 3.0 equiv) in DCM (1.3 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.3 mL). The suspension was treated with 1M HCl (0.53 mL, 19.3 mg, 0.53 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (93 μL, 68 mg, 0.53 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 5% MeOH in DCM) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2h as a clear, colorless oil (29.7 mg, 0.073 mmol, 27%). R_f = 0.39 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d) δ 2.41 (q, J = 1.9 Hz, 3H), 2.90–2.97 (complex, 2H), 3.06–3.13 (complex, 2H), 6.99–7.07 (complex, 2H), 7.11–7.16 (complex, 2H), 7.19 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.22 (s, 1H), 7.38–7.52 (complex, 3H), 7.73 (td, J = 1.8, 7.8 Hz, 1H), 8.10 (dt, J = 1.1, 7.9 Hz, 1H), 8.25 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.2 Hz), 27.1, 33.2, 124.1, 124.2, 124.6 (q, J = 273.9 Hz), 125.8 (q, J = 5.6 Hz), 127.4, 129.1 (q, J = 29.7 Hz), 129.5, 129.5, 131.9, 132.3, 134.8, 135.2, 136.8, 137.9, 146.6, 149.0, 152.9, 155.9, 163.1; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.7. IR (neat) 1588, 1499 cm⁻¹. HRMS calcd for C₂₃H₂₀F₃N₄⁺ [M+H]⁺ 409.1635 found, 409.1639. Purity (HPLC) >99%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (2h).

N-(Pyridin-2-ylmethyl)pyridine-2-carbothioamide (8f) (28 mg, 0.12 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (36 mg, 0.14 mmol, 1.2 equiv), AgOBz (55 mg, 0.24 mmol, 2.0 equiv), and HOAc (22 mg, 0.36 mmol, 3.0 equiv) were stirred at room temperature for 19 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.2 mL). The suspension was treated with 1M HCl (0.51 mL, 19 mg, 0.51 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (91 μL, 66 mg, 0.51 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) followed by (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2i as a clear, orange oil (8.1mg, 0.019 mmol, 16%). R_f = 0.51 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d) δ 2.42 (q, J = 1.9 Hz, 3H), 3.03–3.16 (complex, 4H), 5.95 (s, 2H), 6.94 (d, J = 7.9 Hz, 1H), 7.14–7.21 (complex, 2H), 7.26–7.32 (complex, 2H), 7.37 (s, 1H), 7.54 (td, J = 1.8, 7.7 Hz, 1H), 7.80 (td, J = 1.8, 7.8 Hz, 1H), 8.32–8.36 (m, 1H), 8.49–8.54 (complex, 2H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.1 Hz), 27.1, 32.7, 49.9, 121.4, 123.0, 123.8, 124.2, 124.5 (q, J = 274.5 Hz), 125.8 (q, J = 5.5 Hz), 129.0 (q, J = 29.6 Hz), 131.9, 132.2, 134.7, 137.2, 137.3, 138.3, 147.9, 148.8, 149.5, 151.9, 155.8, 156.6, 163.2; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 2916, 1590 cm⁻¹. HRMS calcd for C₂₃H₂₁F₃N₅⁺ [M+H]⁺ 424.1744, found 424.1740. Purity (HPLC) = 96%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (2i).

N-(Pyridin-3-ylmethyl)pyridine-2-carbothioamide (8g) (26 mg, 0.12 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (34 mg, 0.14 mmol, 1.2 equiv), AgOBz (53 mg, 0.23 mmol, 2.0 equiv), and HOAc (20 μL, 21 mg, 0.34 mmol, 3.0 equiv) in DCM (0.5 mL, 0.2 M) were stirred at room temperature for 15.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.0 mL). The suspension was treated with 1M HCl (0.23 mL, 8.4 mg, 0.23 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (41 μL, 30 mg, 0.23 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2j as a clear, colorless oil (12.3 mg, 0.029 mmol, 25%). R_f = 0.38 (5% MeOH in DCM). ¹H NMR (600 MHz, chloroform-d) δ 2.43 (q, J = 1.9 Hz, 3H), 2.94–2.98 (complex, 2H), 3.14 (t, J = 7.8 Hz, 2H), 5.81 (s, 2H), 7.15–7.21 (complex, 2H), 7.22 (dd, J = 1.9, 7.8 Hz, 1H), 7.26–7.33 (complex, 2H), 7.36 (s, 1H), 7.81 (td, J = 1.8, 7.8 Hz, 1H), 8.34 (dd, J = 1.1, 8.0 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.49–8.52 (complex, 2H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.2 Hz), 27.2, 32.6, 45.9, 123.8, 124.0, 124.4, 124.6 (q, J = 274.1 Hz), 125.8 (q, J = 5.5 Hz), 129.2 (q, J = 29.6 Hz), 131.9, 132.2, 132.4, 134.8, 135.0, 137.4, 138.1, 147.8, 148.0, 148.8, 149.0, 152.0, 155.9; ¹⁹F NMR (471 MHz, chloroform-d) δ −61.6. IR(neat) 1590, 1504 cm⁻¹. HRMS calcd for C₂₃H₂₁F₃N₅⁺ [M+H]⁺ 424.1744, found 424.1747. Purity (HPLC) = 98%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(pyridin-4-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (2j).

N-(Pyridin-4-ylmethyl)pyridine-2-carbothioamide (8h) (78 mg, 0.34 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (100 mg, 0.41 mmol, 1.2 equiv), AgOBz (120 mg, 0.52 mmol, 1.5 equiv), and HOAc (58 μL, 61 mg, 1.0 mmol, 3.0 equiv) in DCM (1.7 mL, 0.2 M) were stirred at room temperature for 16.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (0.35 mL). The suspension was treated with 1M HCl (0.68 mL, 25 mg, 0.68 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (118 μL, 88 mg, 0.68 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Normal phase chromatography (100% hexanes to 100% EtOAc, followed by 100% DCM to 1% MeOH in DCM) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 2k as a clear, colorless oil (6.4 mg, 0.015 mmol, 5%). R_f = 0.36 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d) δ 2.43 (q, J = 1.9 Hz, 3H), 2.88–2.96 (complex, 2H), 3.12–3.20 (complex, 2H), 5.81 (s, 2H), 6.86–6.89 (complex, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.21 (dd, J = 1.6, 7.5 Hz, 1H), 7.28 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.36 (s, 1H), 7.81 (td, J = 1.8, 7.8 Hz, 1H), 8.37 (dt, J = 1.1, 8.0 Hz, 1H), 8.46 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H), 8.48 – 8.52 (m, 2H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.4 Hz), 27.1, 32.6, 47.3, 121.2, 123.7, 124.3, 124.6 (apparent q, J = 271.8 Hz), 125.8 (q, J = 5.5 Hz), 129.2 (q, J = 29.7 Hz), 131.9, 132.4, 135.0, 137.3, 138.1, 145.4, 147.8, 148.8, 150.4, 152.0, 156.0; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.7. IR (neat) 2926, 1674 cm⁻¹. HRMS calcd for C₂₃H₂₁F₃N₅⁺ [M+H]⁺ 424.1744, found 424.1748. Purity (HPLC) >99%.

2-(4-(Cyclopropylmethyl)-5-(4-methyl-3-(trifluoromethyl)phenethyl)-4H-1,2,4-triazol-3-yl)pyridine (2k).

N-(Cyclopropylmethyl)pyridine-2-carbothioamide (8i) (79 mg, 0.41 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (122 mg, 0.50 mmol, 1.2 equiv), AgOBz (189 mg, 0.82 mmol, 2.0 equiv), and HOAc (71 μL, 74 mg, 1.2 mmol, 3.0 equiv) in DCM (2.1 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.1 mL). The suspension was treated with 1M HCl (0.82 mL, 30 mg, 0.82 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (148 μL, 107 mg, 0.82 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 21 as a cream solid (62.1 mg, 0.16 mmol, 39%). R_f = 0.20 (100% EtOAc); mp 60.5–63.3 °C. ¹H NMR (400 MHz, chloroform-d) δ 0.20–0.27 (complex, 2H), 0.40–0.48 (complex, 2H), 1.03–1.13 (m, 1H), 2.45 (d, J = 2.0 Hz, 3H), 3.08–3.16 (complex, 2H), 3.28–3.35 (complex, 2H), 4.43 (d, J = 7.1 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.31–7.38 (complex, 2H), 7.49 (s, 1H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.30 (dt, J = 1.1, 8.0 Hz, 1H), 8.61 (ddd, J = 1.0, 1.9, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 6.6, 14.4, 21.6 (q, J = 2.1 Hz), 30.0, 35.4, 51.3, 126.7, 126.8, 127.2 (q, J = 273.9 Hz), 128.3 (q, J = 5.5 Hz), 131.7 (q, J = 29.7 Hz), 134.5, 135.0, 137.5, 139.8, 140.8, 150.6, 151.3, 154.4, 158.0.;¹⁹F NMR (376 MHz, chloroform-d) δ −61.7. IR (solid) 1588, 1522, 1501, 1476, 1445 cm⁻¹. HRMS calcd for C₂₁H₂₂F₃N₄⁺ [M+H]⁺ 387.1791, found 387.1790. Purity (HPLC) >99%.

3-(4-Methyl-3-(trifluoromethyl)phenethyl)-5-phenyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazole (3a).

N-(Thiophen-2-ylmethyl)benzothioamide (8j) (104 mg, 0.45 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (132 mg, 0.54 mmol, 1.2 equiv), AgOBz (205 mg, 0.90 mmol, 2.0 equiv), and HOAc (77 μL, 81 mg, 1.3 mmol, 3.0 equiv) in DCM (2.2 mL, 0.2 molar) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.2 mL). The suspension was treated with 1M HCl (0.90 mL, 33 mg, 0.90 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (161 μL, 116 mg, 0.90 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) afforded 3a as a clear, colorless oil (81.5 mg, 0.19 mmol, 43%). R_f = 0.25 (100% EtOAc). ¹H NMR (400 MHz, DMSO-d₆) δ 2.40 (s, 3H), 3.06 (s, 4H), 5.46 (s, 2H), 6.77–6.80 (m, 1H), 6.90–6.94 (m, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.42–7.46 (complex, 2H), 7.51–7.56 (complex, 4H), 7.58–7.63 (complex, 2H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.2 Hz), 27.4, 32.8, 43.3, 124.6 (q, J = 273.9 Hz), 125.80 (q, J = 5.5 Hz), 126.1, 126.3, 126.7, 127.5, 129.1 (apparent q (overlapping with peaks at 129.9), J = 14.8 Hz), 129.18, 129.25, 130.6, 132.0, 132.4, 134.9 (d, J = 2.1 Hz), 137.5, 138.2, 154.6, 154.8; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.6; IR (neat) 1505, 1477 cm⁻¹. HRMS calcd for C₂₃H₂₁F₃N₃S⁺ [M+H]⁺ 428.1403, found 428.1396. Purity (HPLC) >99%.

3-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (3b).

N-(Thiophen-2-ylmethyl)pyridine-3-carbothioamide (8k) (63 mg, 0.27 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (79 mg, 0.32 mmol, 1.2 equiv), AgOBz (122 mg, 0.53 mmol, 2.0 equiv), and HOAc (46 μL, 48 mg, 0.80 mmol, 3.0 equiv) in DCM (1.4 mL, 0.2 M) were stirred at room temperature for 16 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.4 mL). The suspension was treated with 1M HCl (0.53 mL, 20 mg, 0.53 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (96 μL, 69 mg, 0.53 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EA) followed by preparatory TLC (5% MeOH in DCM) afforded 3b as a clear, colorless oil (27.8 mg, 0.065 mmol, 24%). R_f = 0.29 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d) δ 2.45 (d, J = 1.9 Hz, 3H), 3.09–3.16 (complex, 2H), 3.17–3.24 (complex, 2H), 5.24 (s, 2H), 6.71 (d, J = 3.2 Hz, 1H), 6.95 (dd, J = 3.5, 5.1 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.27–7.32 (m, 2H), 7.36 (s, 1H), 7.54 (dd, J = 5.0, 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.78 (d, J = 5.0 Hz, 1H), 8.86 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.2 Hz), 27.2, 32.6, 43.9, 123.6, 124.6, 124.6 (q, J = 273.93), 125.8 (q, J = 5.5 Hz), 126.5, 126.9, 127.8, 129.2 (q, J = 29.7), 132.0, 132.5, 135.2, 136.4, 137.6, 138.5, 147.8, 150.1, 151.5, 155.5; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR(neat) 1504, 1454 cm⁻¹. HRMS calcd for C₂₂H₂₀F₃N₄S⁺ [M+H]⁺ 429.1355, found 429.1359. Purity (HPLC) >99%.

4-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (3c).

N-(Thiophen-2-ylmethyl)pyridine-4-carbothioamide (8l) (27 mg, 0.11 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (33 mg, 0.14 mmol, 1.2 equiv), AgOBz (52 mg, 0.23 mmol, 2.0 equiv), and HOAc (20 μL, 20 mg, 0.34 mmol, 3.0 equiv) in DCM (0.6 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (0.6 mL). The suspension was treated with 1M HCl (0.23 mL, 8.2 mg, 0.23 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (40 μL, 29 mg, 0.23 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 3c as a white solid (23.7 mg, 0.055 mmol, 49%). R_f = 0.12 (5% MeOH in DCM); mp 156.9–166.2 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.40 (q, J = 2.1 Hz, 3H), 3.04–3.15 (complex, 4H), 5.58 (s, 2H), 6.81 (dd, J = 1.3, 3.5 Hz, 1H), 6.92 (dd, J = 3.5, 5.1 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.43–7.47 (complex, 2H), 7.55 (s, 1H), 7.63–7.67 (complex, 2H), 8.71–8.76 (complex, 2H); ¹³C NMR (151 MHz, DMSO-d₆) δ 18.4, 25.9, 31.5, 42.4, 122.5, 124.7 (q, J = 273.7 Hz), 125.7 (q, J = 5.5 Hz), 126.3, 126.4, 127.2, 127.3 (q, J = 29.0 Hz), 132.2, 132.5, 133.7, 134.8, 138.3, 138.9, 150.4, 151.6, 155.3; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.6. IR (solid) 1607, 1529 cm⁻¹. HRMS calcd for C₂₂H₂₀F₃N₄S⁺ [M+H]⁺ 429.1355, found 429.1347. Purity (HPLC) >99%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyrimidine (3d).

N-(Thiophen-2-ylmethyl)pyrimidine-2-carbothioamide (8m) (80 mg, 0.34 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (100 mg, 0.41 mmol, 1.2 equiv), AgOBz (155 mg, 0.68 mmol, 2.0 equiv), and HOAc (58 μL, 61 mg, 1.0 mmol, 3.0 equiv) in DCM (1.7 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.7 mL). The suspension was treated with 1M HCl (0.68 mL, 25 mg, 0.68 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (122 μL, 88 mg, 0.68 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 3d as a cream solid (40.7 mg, 0.095 mmol, 28%). R_f = 0.21 (5% MeOH in DCM); mp 157.5–164.5 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.40 (d, J = 2.1 Hz, 3H), 3.05–3.13 (complex, 2H), 3.13–3.21 (complex, 2H), 5.94 (s, 2H), 6.91 (dd, J = 3.5, 5.1 Hz, 1H), 7.00 (dd, J = 1.2, 3.5 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 1.3, 5.1 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.63 (td, J = 0.8, 4.9 Hz, 1H), 9.0 (s, 1H), 9.01 (s, 1H); ¹³C NMR (151 MHz, DMSO-d₆) δ 18.36 (d, J = 2.2 Hz), 26.0, 31.3, 42.7, 121.5, 124.7 (q, J = 273.8 Hz), 125.7 (q, J = 5.6 Hz), 126.7, 126.8, 127.0, 127.2 (q, J = 29.0 Hz) 132.2, 132.5, 133.7, 138.7, 138.9, 150.5, 155.5, 155.9, 157.9; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.6. IR (solid) 1559, 1489 cm⁻¹. HRMS calcd for C₂₁H₁₉F₃N₅S⁺ [M+H]⁺ 430.1308, found 430.1305. Purity (HPLC) >99%.

4-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyrimidine (3e).

N-(Thiophen-2-ylmethyl)pyrimidine-4-carbothioamide (8n) (74 mg, 0.31 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (93 mg, 0.38 mmol, 1.2 equiv), AgOBz (144 mg, 0.63 mmol, 2.0 equiv), and HOAc (54 μL, 56 mg, 1.0 mmol, 3.0 equiv) in DCM (1.6 mL, 0.2 M) were stirred at room temperature for 20.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.6 mL, 0.2 M). The suspension was treated with 1M HCl (0.63 mL, 23 mg, 0.63 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (112 μL, 81 mg, 0.63 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reversed phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) followed by prep TLC (5% MeOH in DCM) afforded 3e as a white solid (27.3 mg, 0.064 mmol, 20%). R_f = 0.34 (5% MeOH in DCM); mp 151.0–155.1 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.45 (q, J = 1.9 Hz, 3H), 3.09–3.15 (complex, 2H), 3.16–3.21 (complex, 2H), 5.97 (s, 2H), 6.88 (dt, J = 1.1, 3.6 Hz, 1H), 6.91 (dd, J = 3.5, 5.1 Hz, 1H), 7.18–7.25 (complex, 2H), 7.28 (dd, J = 1.9, 7.5 Hz, 1H), 7.43 (s, 1H), 8.33 (dd, J = 1.4, 5.3 Hz, 1H), 8.88 (d, J = 5.3 Hz, 1H), 9.27 (d, J = 1.5 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.1 Hz), 27.2, 32.6, 43.7, 119.5, 124.6 (q, J = 273.8 Hz), 125.8 (q, J = 5.5 Hz), 126.5, 126.8, 127.0, 129.2 (q, J = 29.7 Hz), 131.9, 132.4, 135.0 (d, J = 1.9 Hz), 137.9, 138.1, 149.7, 154.8, 157.0, 158.2, 158.4; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.7. IR (solid) 3090, 1584 cm⁻¹. HRMS calcd for C₂₁H₁₉F₃N₅S⁺ [M+H]⁺ 430.1308, found 430.1301. Purity (HPLC) >99%.

3-Methyl-2-(5-(4-methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (3f).

3-Methyl-N-(thiophen-2-ylmethyl)pyridine-2-carbothioamide (8o) (63 mg, 0.25 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (75 mg, 0.30 mmol, 1.2 equiv), AgOBz (116 mg, 0.51 mmol, 2.0 equiv), and HOAc (45 mg, 0.76 mmol, 3.0 equiv) in DCM (1.2 mL, 0.2 M) were stirred at room temperature for 17 hours. The reaction was concentrated, and the resulting oil was suspended in methanol (1.2 mL). The suspension was treated with 1M HCl (0.51 mL, 19 mg, 0.51 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (91 μL, 66 mg, 0.51 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAC followed by 100% DCM to 0.8% MeOH in DCM) afforded 3f as a clear, colorless oil (15 mg, 0.035 mmol, 14%). R_f = 0.52 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d) δ 2.45 (q, J = 1.9 Hz, 3H), 2.55 (s, 3H), 3.06–3.14 (m, 2H), 3.15–3.22 (m, 2H), 5.56 (d, J = 0.9 Hz, 2H), 6.69 (dt, J = 1.1, 3.6 Hz, 1H), 6.85 (dd, J = 3.5, 5.1 Hz, 1H), 7.17 (dd, J = 1.2, 5.1 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.26–7.33 (complex, 2H), 7.43 (s, 1H), 7.67 (ddd, J = 0.8, 1.7, 7.7 Hz, 1H), 8.54 (ddd, J = 0.7, 1.7, 4.8 Hz, 1H); ¹³C NMR (126 MHz, chloroform-d) δ 19.0 (q, J = 2.1 Hz), 20.1, 27.3, 32.7, 43.1, 124.3, 124.6 (q, J = 274.3 Hz), 125.8 (q, J = 5.6 Hz), 126.5, 126.5, 126.9, 129.1 (q, J = 29.7 Hz), 131.9, 132.4, 134.9 (q, J = 1.8 Hz), 135.6, 138.1, 138.3, 139.6, 145.9 146.5, 151.8, 154.3; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 2916, 2849 cm⁻¹. HRMS calcd for C₂₃H₂₂F₃N₄S⁺ [M+H]⁺ 443.1512, found 443.1523. Purity (HPLC) = 96%.

3-(4-Methyl-3-(trifluoromethyl)phenethyl)-5-(naphthalen-1-yl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazole (3g).

N-(Thiophen-2-ylmethyl)naphthalene-1-carbothioamide (8p) (73 mg, 0.26 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (76 mg, 0.31 mmol, 1.2 equiv), AgOBz (118 mg, 0.52 mmol, 2.0 equiv), and HOAc (44μL, 46 mg, 0.77 mmol, 3.0 equiv) were stirred at room temperature for 16 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.52 mL, 19 mg, 0.52 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (92 μL, 67 mg, 0.52 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) afforded 3g as a clear, colorless oil (21.1 mg, 0.044 mmol, 17%). R_f = 0.50 (100% EtOAc). ¹H NMR (400 MHz, chloroform-d) δ 2.47 (q, J = 1.9 Hz, 3H), 3.05–3.14 (complex, 2H), 3.18–3.25 (complex, 2H), 4.88 (s, 2H), 6.46–6.52 (m, 1H), 6.80 (dd, J = 3.5, 5.1 Hz, 1H), 7.16 (dd, J = 1.2, 5.1 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.44 (s, 1H), 7.46–7.59 (complex, 5H), 7.92 (dt, J = 1.0, 8.2 Hz, 1H), 8.01 (dd, J = 2.1, 7.6 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.0 (q, J = 2.1 Hz), 27.7, 33.1, 42.8, 124.1 (apparent q, J = 124.1 Hz), 125.1, 125.2, 126.3, 126.5, 126.8, 127.2, 127.5, 128.6, 129.2 (q, J = 29.8 Hz), 129.4, 131.1, 132.0, 132.4, 133.7, 134.9 (d, J = 1.4 Hz), 137.4, 138.4, 153.5, 154.2; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 3043, 1503 cm⁻¹. HRMS calcd for C₂₇H₂₃F₃N₃S⁺ [M+H]⁺ 478.1559, found 478.1545. Purity (HPLC) = 99%.

3-(4-Methyl-3-(trifluoromethyl)phenethyl)-5-(naphthalen-2-yl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazole (3h).

N-(Thiophen-2-ylmethyl)naphthalene-2-carbothioamide (8q) (81 mg, 0.29 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (84 mg, 0.34 mmol, 1.2 equiv), AgOBz (131 mg, 0.57 mmol, 2.0 equiv), and HOAc (49 μL, 52 mg, 0.86 mmol, 3.0 equiv) in DCM (1.5 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (4.5 mL). The suspension was treated with 1M HCl (0.57 mL, 21 mg, 0.57 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (102 μL, 74 mg, 0.57 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 3h as a white solid (22.4 mg, 0.047 mmol, 16%). R_f = 0.31 (5% MeOH in DCM); mp 142.0–147.7°C. ¹H NMR (400 MHz, chloroform-d) δ 2.45 (d, J = 1.9 Hz, 3H), 3.01–3.09 (complex, 2H), 3.14–3.22 (complex, 2H), 5.19 (s, 2H), 6.72 (dt, J = 1.2, 3.6 Hz, 1H), 6.95 (dd, J = 3.5, 5.1 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.25–7.31 (complex, 2H), 7.38 (s, 1H), 7.50–7.62 (complex, 2H), 7.68 (dd, J = 1.7, 8.4 Hz, 1H), 7.80–7.86 (m, 1H), 7.86 – 7.92 (m, 1H), 7.94 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (d, J = 2.2 Hz), 27.5, 32.9, 43.3, 124.3, 124.6 (q, J = 273.4 Hz), 125.8 (apparent q overlapping with peak at 125.9, J = 5.5 Hz), 125.9, 126.0, 126.3, 127.1, 127.5, 127.6, 128.0, 128.7, 129.1, 129.2, 120.4 (apparent q overlapping with peak at 120.4, J = 29.8 Hz), 132.0, 132.4, 133.0, 134.0, 134.9, 137.8, 138.3, 154.7, 155.0; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 2947, 1603 cm⁻¹. HRMS calcd for C₂₇H₂₃F₃N₃S⁺ [M+H]⁺ 478.1559, found 478.1549. Purity (HPLC) >99%.

2-(5-(4-Methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)quinoline (3i).

N-(Thiophen-2-ylmethyl)quinoline-2-carbothioamide (8r) (75 mg, 0.26 mmol, 1.0 equiv), 3-(4-methyl-3-(trifluoromethyl)phenyl)propanehydrazide (9b) (78 mg, 0.32 mmol, 1.2 equiv), AgOBz (121 mg, 0.53 mmol, 2.0 equiv), and HOAc (45 μL, 48 mg, 0.78 mmol, 3.0 equiv) in DCM (1.3 mL, 0.2 M) were stirred at room temperature for 17.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.3 mL). The suspension was treated with 1M HCl (0.53 mL, 19 mg, 0.53 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (95 μL, 68 mg, 0.53 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) followed by prep TLC (5% MeOH in DCM) afforded 3i as a cream solid (10.3 mg, 0.021 mmol, 8%). R_f = 0.28 (5% MeOH in DCM); mp 154.2–162.4 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.46 (d, J = 1.9 Hz, 3H), 3.13–3.25 (complex, 4H), 6.16 (s, 2H), 6.90 (dd, J = 3.5, 5.1 Hz, 1H), 6.97 (dd, J = 1.2, 3.6 Hz, 1H), 7.18–7.24 (complex, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.60 (ddd, J = 1.2, 6.9, 8.1 Hz, 1H), 7.74 (ddd, J = 1.5, 6.9, 8.4 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.08 (d, J = 2.2 Hz), 27.3, 32.7, 44.0, 120.9, 124.7 (q, J = 273.7 Hz), 125.8 (q, J = 5.5 Hz), 126.6, 126.8, 127.0, 127.6, 128.0, 128.1, 129.2 (q, J = 29.7 Hz), 129.6, 130.2, 132.0, 132.4, 134.9, 137.2, 138.3, 138.4, 147.1, 147.9, 151.4, 156.2; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (neat) 2928, 1600 cm⁻¹. HRMS calcd for C₂₆H₂₂F₃N₄S⁺ [M+H]⁺ 479.1512, found 479.1522. Purity (HPLC) >99%.

3-(1-Methyl-1H-imidazol-2-yl)-5-(4-methyl-3-(trifluoromethyl)phenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazole (3j).

3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiophen-2-ylmethyl)propanethioamide (8s) (176 mg, 0.51 mmol, 1.0 equiv), 1-methyl-1H-imidazole-2-carbohydrazide (86 mg, 0.61 mmol, 1.2 equiv), AgOBz (235 mg, 1.0 mmol, 2.0 equiv), and HOAc (88 μL, 92 mg, 1.5 mmol, 3.0 equiv) in DCE (2.6 mL, 0.2 M) were reacted stirred at 60°C for 2.5 days. The reaction was concentrated, and the resulting oil was suspended in methanol (2.6 mL). The suspension was treated with 1M HCl (1.0 mL, 37 mg, 1.0 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (183 μL, 133 mg, 1.0 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 3j as a white solid (78.5 mg, 0.18 mmol, 35%). R_f = 0.44 (5% MeOH in DCM); mp 83.8–88.1 °C. ¹H NMR (600 MHz, chloroform-d) δ 2.45 (s, 3H), 3.07–3.15 (complex, 2H), 3.16–3.21 (complex, 2H), 4.04 (s, 3H), 5.93 (s, 2H), 6.85–6.91 (complex, 2H), 7.07 (s, 1H), 7.18 (dd, J = 1.5, 4.8 Hz, 1H), 7.19–7.24 (complex, 2H), 7.31 (dd, J = 1.8, 7.8 Hz, 1H), 7.43 (s, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.1 (q, J = 2.2 Hz), 27.2, 32.5, 36.0, 43.3, 124.1, 124.6 (q, J = 273.9 Hz), 125.8 (q, J = 5.5 Hz), 126.4, 127.0, 127.1, 127.9, 129.2 (q, J = 29.8 Hz), 131.9, 132.4, 135.0, 135.3, 137.7 (d, J = 2.7 Hz), 138.1, 144.9, 154.7; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.6. IR (solid) 1505, 1457 cm⁻¹. HRMS calcd for C₂₁H₂₁F₃N₅S⁺ [M+H]⁺ 432.1464 found, 432.1465. Purity (HPLC) >99%.

2-(5-Phenethyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4a).

3-Phenyl-N-(thiophen-2-ylmethyl)propanethioamide (8t) (94 mg, 0.36 mmol, 1.0 equiv), picolinohydrazide (59 mg, 0.43 mmol, 1.2 equiv), AgOBz (165 mg, 0.72 mmol, 2.0 equiv), and HOAc (62 μL, 65 mg, 1.1 mmol, 3.0 equiv) in DCM (1.8 mL, 0.2 molar) were stirred at room temperature for 16 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.8 mL). The suspension was treated with 1M HCl (1.8 mL, 66 mg, 1.8 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (314 μL, 233 mg, 1.8 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1 % formic acid in water to 100% acetonitrile) afforded 4a as a cream solid (71.5 mg, 0.21 mmol, 57%). R_f = 0.51 (5% MeOH in DCM); mp 109.2–113.7 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.08–3.21 (complex, 4H), 5.89 (s, 2H), 6.85 (dd, J = 1.2, 3.5 Hz, 1H), 6.88 (dd, J = 3.5, 5.1 Hz, 1H), 7.18 (dd, J = 1.3, 5.1 Hz, 1H), 7.20–7.25 (complex, 3H), 7.28–7.37 (complex, 3H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.33 (dt, J = 1.1, 8.0 Hz, 1H), 8.64 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 27.5, 33.6, 43.3, 123.8, 124.2, 126.2, 126.6, 126.6, 126.8, 128.6, 128.8, 137.2, 138.7, 140.8, 148.2, 148.7, 151.5, 156.2. IR (solid) 1587, 1498 cm⁻¹. HRMS calcd for C₂₀H₁₉N₄S⁺ [M+H]⁺ 347.1325, found 347.1324. Purity (HPLC) >99%.

2-(5-(4-Methoxyphenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4b).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (61 mg, 0.26 mmol, 1.0 equiv), 3-(4-methoxyphenyl)propanehydrazide (9d) (60 mg, 0.31 mmol, 1.2 equiv), AgOBz (118 mg, 0.52 mmol, 2.0 equiv), and HOAc (44 μL, 47 mg, 0.78 mmol, 3.0 equiv) in DCM (1.3 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.3 mL). The suspension was treated with 1M HCl (0.52 mL, 19 mg, 0.52 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (90 μL, 67 mg, 0.52 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 4b as a cream solid (41.7 mg, 0.11 mmol, 42%). R_f = 0.42 (5% MeOH in DCM); mp 126.9–133.6 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.07–3.12 (complex, 4H), 3.79 (s, 3H), 5.87 (s, 2H), 6.81–6.86 (complex, 3H), 6.88 (dd, J = 3.5, 5.1 Hz, 1H), 7.11–7.16 (complex, 2H), 7.18 (dd, J = 1.3, 5.1 Hz, 1H), 7.35 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.32 (dt, J = 1.1, 8.0 Hz, 1H), 8.64 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 27.7, 32.9, 43.4, 55.4, 114.2, 123.8, 124.3, 126.3, 126.6, 126.8, 129.6, 132.7, 137.3, 138.5, 148.0, 148.7, 151.4, 156.3, 158.4, 163.2. IR (solid) 2932, 1610 cm⁻¹. HRMS calcd for C₂₁H₂₁N₄OS⁺ [M+H]⁺ 377.1431, found 377.1434. Purity (HPLC) >99%.

2-(5-(4-Fluorophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4c).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (91 mg, 0.39 mmol, 1.0 equiv), 3-(4-fluorophenyl)propanehydrazide (9e) (85 mg, 47 mmol, 1.2 equiv), AgOBz (178 mg, 0.78 mmol, 2.0 equiv), and HOAc (67 μL, 70 mg, 1.2 mmol, 3.0 equiv) in DCM (2.0 mL, 0.2 M) were stirred at room temperature for 24 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.78 mL, 28 mg, 0.78 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (68 μL, 50 mg, 0.39 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 4c as a white solid (19.8 mg, 0.054 mmol, 14%). R_f = 0.51 (5% MeOH in DCM); mp 113.4–118.1°C. ¹H NMR (400 MHz, chloroform-d) δ 3.16 (s, 4H), 5.93 (s, 2H), 6.84–6.87 (m, 1H), 6.90 (dd, J = 3.6, 5.1 Hz, 1H), 6.93–7.03 (complex, 2H), 7.10–7.24 (complex, 3H), 7.34–7.42 (m, 1H), 7.81–7.90 (m, 1H), 8.35 (dt, J = 1.0, 8.0 Hz, 1H), 8.66 (ddt, J = 0.8, 1.7, 4.8 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 27.4, 32.6, 43.7, 115.6 (d, J = 21.4 Hz), 124.1, 124.8, 126.6, 126.9, 130.09 (d, J = 7.8 Hz), 135.9 (d, J = 3.4 Hz), 137.5, 137.8, 147.3, 148.8, 151.2, 155.9, 161.0, 162.6; ¹⁹F NMR (376 MHz, chloroform-d) δ −116.4. IR (solid) 1588, 1508 cm⁻¹. HRMS calcd for C₂₀H₁₈FN₄S⁺ [M+H]⁺ 365.1231, found 365.1216. HPLC purity = 95%.

2-(5-(4-Chlorophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4d).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (100 mg, 0.43 mmol, 1.0 equiv), 3-(4-chlorophenyl)propanehydrazide (9f) (102 mg, 0.51 mmol, 1.2 equiv), AgOBz (196 mg, 0.86 mmol, 2.0 equiv), and HOAc (73 μL, 77 mg, 1.3 mmol, 3.0 equiv) in DCM (2.1 mL, 0.2 M) were stirred at room temperature for 19 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.1 mL). The suspension was treated with 1M HCl (0.86 mL, 31 mg, 0.86 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (153 μL, 111 mg, 0.86 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 4d as a white solid (39.6 mg, 0.10 mmol, 24%). R_f = 0.46 (5% MeOH in DCM); mp 148.8–153.7 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.98–3.06 (complex, 2H), 3.09–3.15 (complex, 2H), 6.03 (s, 2H), 6.93 (dd, J = 3.5, 5.1 Hz, 1H), 7.03 (dd, J = 1.3, 3.5 Hz, 1H), 7.31 (q, J = 8.6 Hz, 4H), 7.41 (dd, J = 1.3, 5.1 Hz, 1H), 7.53 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 8.00 (td, J = 1.8, 7.8 Hz, 1H), 8.16 (dt, J = 1.2, 8.0 Hz, 1H), 8.72 (dt, J = 1.3, 4.8 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 27.2, 32.7, 43.7, 124.0, 124.7, 126.6, 126.88, 126.92, 128.9, 130.0, 132.5, 137.5, 137.9, 138.8, 147.4, 148.8, 151.2, 155.8. IR (solid) 1588, 1528 cm⁻¹. HRMS calcd for C₂₀H₁₈ClN₄S⁺ [M+H]⁺ 381.0935 found, 381.0938. Purity (HPLC) >99%.

2-(5-(4-Bromophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4e).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (103 mg, 0.44 mmol, 1.0 equiv), 3-(4-bromophenyl)propanehydrazide (9g) (128 mg, 0.53 mmol, 1.2 equiv), AgOBz (202 mg, 0.88 mmol, 2.0 equiv), and HOAc (76 μL, 79 mg, 1.3 mmol, 3.0 equiv) in DCM (2.1 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.1 mL). The suspension was treated with 1M HCl (0.88 mL, 32 mg, 0.88 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (158 μL, 114 mg, 0.88 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 4e as a white solid (29.2 mg, 0.069 mmol, 16%). R_f = 0.49 (1:3 DCM:EA); mp 166.39–169.57 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.15 (s, 4H), 5.96 (s, 2H), 6.84–6.86 (m, 1H), 6.88–6.92 (m, 1H), 7.06–7.14 (m, 2H), 7.21 (dd, J = 1.3, 5.1 Hz, 1H), 7.34–7.44 (complex, 3H), 7.86 (td, J = 1.8, 7.8 Hz, 1H), 8.35 (dt, J = 1.1, 8.0 Hz, 1H), 8.66 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 27.1, 32.7, 43.8, 120.6, 124.1, 124.7, 126.6, 126.90, 126.93, 130.4, 131.9, 137.5, 137.9, 139.3, 147.4, 148.8, 151.2, 155.8. IR (solid) 1588, 1532 cm⁻¹. HRMS calcd for C₂₀H₁₈BrN₄S⁺ [M+H]⁺ 425.0430 found, 425.0435. Purity (HPLC) >99%.

2-(5-(3-Bromophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4f).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (61 mg, 0.26 mmol, 1.0 equiv), 3-(3-bromophenyl)propanehydrazide (9h) (76 mg, 0.31 mmol, 1.2 equiv), AgOBz (120 mg, 0.52 mmol, 2.0 equiv), and HOAc (45 μL, 47 mg, 0.78 mmol, 3.0 equiv) in DCM (1.4 mL, 0.2 M) were stirred at room temperature for 16.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.4 mL). The suspension was treated with 1M HCl (0.52 mL, 19 mg, 0.52 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (94 μL, 68 mg, 0.52 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) followed by prep TLC (5%MeOH in DCM) afforded 4f as a white solid (37.3 mg, 0.087 mmol, 34%). R_f = 0.43 (5% MeOH in DCM); mp 125.3–131.8 °C. ¹H NMR (500 MHz, chloroform-d) δ 3.07–3.19 (complex, 4H), 5.95 (s, 2H), 6.84–6.88 (m, 1H), 6.90 (dd, J = 3.5, 5.1 Hz, 1H), 7.15–7.18 (complex, 2H), 7.20 (dd, J = 1.3, 5.1 Hz, 1H), 7.33–7.39 (complex, 3H), 7.84 (td, J = 1.8, 7.8 Hz, 1H), 8.34 (dd, J = 1.2, 8.0 Hz, 1H), 8.65 (ddd, J = 1.0, 1.8, 5.0 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 27.2, 33.0, 43.5, 122.8, 123.9, 124.4, 126.4, 126.7, 126.9, 127.4, 128.6, 128.8, 129.8, 130.4, 131.6, 137.3, 138.4, 143.0, 148.7, 151.5, 155.7. IR (solid) 2917, 1588 cm⁻¹. HRMS calcd for C₂₀H₁₈BrN₄S⁺ [M+H]⁺ 425.0430, found 425.0420. Purity (HPLC) >99%.

2-(5-(2-Bromophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4g).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (70 mg, 0.30 mmol, 1.0 equiv), 3-(2-bromophenyl)propanehydrazide (9i) (87 mg, 0.36 mmol, 1.2 equiv), AgOBz (137 mg, 0.60 mmol, 2.0 equiv), and HOAc (51 μL, 54 mg, 0.90 mmol. 3.0 equiv) in DCM (1.3 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.3 mL). The suspension was treated with 1M HCl (0.60 mL, 22 mg, 0.60 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (104 μL, 77 mg, 0.60 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Normal phase chromatography (100% hexanes to 100% EtOAc) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 4g as a white oil (48.8 mg, 0.12 mmol, 38%). R_f = 0.44 (5% MeOH in DCM). ¹HNMR (400 MHz, DMSO-d₆) δ 3.08–3.21 (complex, 4H), 6.02 (s, 2H), 6.93 (dd, J = 3.5, 5.1 Hz, 1H), 7.01 (dd, J = 1.2, 3.5 Hz, 1H), 7.18 (td, J = 1.9, 7.7 Hz, 1H), 7.33 (td, J = 1.3, 7.4 Hz, 1H), 7.36–7.42 (complex, 2H), 7.53 (ddd, J = 1.3, 4.9, 7.6 Hz, 1H), 7.61 (dd, J = 1.3, 8.0 Hz, 1H), 8.00 (td, J = 1.8, 7.7 Hz, 1H), 8.16 (dt, J = 1.1, 8.0 Hz, 1H), 8.72 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 25.6, 34.4, 43.3, 123.8, 124.2, 124.4, 126.2, 126.6, 126.8, 128.0, 128.5, 131.2, 133.1, 137.2, 138.7, 139.9, 148.3, 148.7, 151.6, 155.9. IR (neat) 3051, 1589 cm⁻¹. HRMS calcd for C₂₀H₁₈BrN₄S⁺ [M+H]⁺ 425.0430, found 425.0424. Purity (HPLC) >99%.

2-(4-(Thiophen-2-ylmethyl)-5-(2-(trifluoromethyl)phenethyl)-4H-1,2,4-triazol-3-yl)pyridine (4h).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (60 mg, 0.26 mmol, 1.0 equiv), 3-(2-(trifluoromethyl)phenyl)propanehydrazide (9j) (72 mg, 0.31 mmol, 1.2 equiv), AgOBz (118 mg, 0.52 mmol, 2.0 equiv), and HOAc (44 μL, 46 mg, 0.78 mmol, 3.0 equiv) in DCM (1.3 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.3 mL). The suspension was treated with 1M HCl (0.52 mL, 19 mg, 0.52 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (90 μL, 67 mg, 0.52 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) followed by preparatory TLC (1:3 DCM:EtOAc) afforded 4h as a white oil (31.2 mg, 0.075 mmol, 29%). R_f = 0.49 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d) δ 3.11–3.20 (complex, 2H), 3.36–3.47 (complex, 2H), 5.92 (s, 2H), 6.81–6.83 (m, 1H), 6.83–6.86 (m, 1H), 7.15 (dd, J = 1.3, 5.0 Hz, 1H), 7.30–7.37 (complex, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.44–7.52 (m, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.84 (td, J = 1.8, 7.8 Hz, 1H), 8.33 (dt, J = 1.1, 8.0 Hz, 1H), 8.65 (d, J = 4.1 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 27.1, 30.7, 43.7, 124.2, 124.8 (q, J = 273.8 Hz), 124.8, 126.3 (q, J = 5.7 Hz), 126.6, 126.9, 127.0, 127.1, 128.6 (q, J = 29.69 Hz), 132.0, 132.5, 137.5, 137.7, 138.8, 147.3, 148.8, 151.2, 155.7; ¹⁹F NMR (376 MHz, chloroform-d) δ −59.4. IR (neat) 1589, 1525 cm⁻¹. HRMS calcd for C₂₁H₁₈F₃N₄S⁺ [M+H]⁺ 415.1199, found 415.1195. Purity (HPLC) >99%.

2-(5-(2,4-Dichlorophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4i).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (40 mg, 0.17 mmol, 1.0 equiv), 3-(2,4-dichlorophenyl)propanehydrazide (9k) (48 mg, 0.21 mmol, 1.2 equiv.), AgOBz (79 mg, 0.34 mmol, 2.0 equiv), and HOAc (30 μL, 31 mg, 0.52 mmol, 3.0 equiv) in DCM (0.9 mL, 0.2 M) were stirred at room temperature for 15 h. The reaction was concentrated, and the resulting oil was suspended in methanol (0.9 mL). The suspension was treated with 1M HCl (0.34 mL, 13 mg, 0.34 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (62 μL, 45 mg, 0.34 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) followed by preparatory TLC (5% MeOH in DCM) afforded 4i as a clear, colorless oil (22.7 mg, 0.055 mmol, 32%). R_f = 0.27 (100% EtOAc). ¹H NMR (400 MHz, DMSO-d₆) δ 3.14 (q, J = 3.2 Hz, 4H), 6.04 (s, 2H), 6.93 (dd, J = 3.5, 5.1 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 7.33–7.44 (complex, 3H), 7.53 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 8.00 (td, J = 1.8, 7.8 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 4.5 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 25.0, 31.0, 43.8, 124.1, 124.7, 126.6, 126.9, 126.9, 127.6, 129.5, 132.2, 133.4, 134.6, 136.3, 137.5, 137.8, 147.4, 148.8, 151.3, 155.5. IR (neat) 1589, 1568 cm⁻¹. HRMS calcd for C₂₀H₁₇Cl₂N₄S⁺ [M+H]⁺ 415.0545, found 415.0539. Purity (HPLC) >99%.

2-(5-(3,4-Dichlorophenethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4j).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (87 mg, 0.33 mmol, 1.0 equiv), 3-(3,4-dichlorophenyl)propanehydrazide (9l) (93 mg, 0.40 mmol, 1.2 equiv), AgOBz (152 mg, 0.66 mmol, 2.0 equiv), and HOAc (57 μL, 60 mg, 0.99 mmol, 3.0 equiv) in DCM (1.7 mL, 0.2 M) were stirred at room temperature for 15 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.1 mL). The suspension was treated with 1M HCl (0.66 mL, 24 mg, 0.66 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (119 μL, 86 mg, 0.66 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 4j as a white solid (41.2 mg, 0.099 mmol, 30%). R_f = 0.23 (100% EtOAc); mp 141.6–144.2 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.14 (s, 4H), 6.00 (s, 2H), 6.85–6.88 (m, 1H), 6.89–6.92 (m, 1H), 7.07 (dd, J = 2.1, 8.2 Hz, 1H), 7.22 (dd, J = 1.3, 5.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.38 (ddd, J = 1.1, 4.8, 7.6 Hz, 1H), 7.85 (td, J = 1.8, 7.8 Hz, 1H), 8.34 (dt, J = 1.1, 8.1 Hz, 1H), 8.66 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 26.9, 32.2, 43.8, 124.0, 124.6, 126.5, 126.8, 127.0, 128.2, 130.6, 130.7, 130.7, 132.6, 137.4, 138.0, 140.6, 147.6, 148.8, 151.4, 155.5. IR (solid) 1588, 1504 cm⁻¹. HRMS calcd for C₂₀H₁₇Cl₂N₄S⁺ [M+H]⁺ 415.0545, found 415.0551. Purity (HPLC) = 98.7%.

2-(5-(2-(Naphthalen-1-yl)ethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4k).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (60 mg, 0.26 mmol, 1.0 equiv), 3-(naphthalen-1-yl)propanehydrazide (9m) (66 mg, 0.31 mmol, 1.2 equiv), AgOBz (118 mg, 0.52 mmol, 2.0 equiv), and HOAc (44μL, 46 mg, 0.78 mmol, 3.0 equiv) were stirred at room temperature for 16 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.3 mL). The suspension was treated with 1M HCl (0.52 mL, 19 mg, 0.52 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (90 μL, 67 mg, 0.52 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) followed by preparatory TLC (100% EtOAc) followed by preparatory TLC (5% MeOH in DCM) afforded 4k as a white oil (34.3 mg, 0.086 mmol, 33%). R_f = 0.64 (5% MeOH in DCM). ¹H NMR (400 MHz, chloroform-d δ 3.24–3.33 (complex, 2H), 3.63–3.72 (complex, 2H), 5.72 (s, 2H), 6.71 (dd, J = 1.2, 3.5 Hz, 1H), 6.83 (dd, J = 3.5, 5.1 Hz, 1H), 7.15 (dd, J = 1.2, 5.1 Hz, 1H), 7.31–7.45 (complex, 3H), 7.45–7.58 (complex, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.80–7.91 (complex, 2H), 8.01–8.08 (m, 1H), 8.35 (dt, J = 1.1, 8.0 Hz, 1H), 8.62 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d δ 26.6, 30.9, 43.3, 123.5, 123.9, 124.3, 125.8, 125.9, 126.3, 126.5, 126.5, 126.6, 126.8, 127.6, 129.1, 131.7, 134.1, 136.6, 137.3, 138.4, 148.0, 148.7, 151.4, 156.4. IR (neat) 3047, 1589 cm⁻¹. HRMS calcd for C₂₄H₂₁F₃N₄S⁺ [M+H]⁺ 397.1481, found 397.1479. HPLC purity = 97%.

2-(5-(2-(Naphthalen-2-yl)ethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (4l).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (99 mg, 0.42 mmol, 1.0 equiv), 3-(naphthalen-2-yl)propanehydrazide (9n) (109 mg, 0.51 mmol, 1.2 equiv.), AgOBz (193 mg, 0.85 mmol, 2.0 equiv), and HOAc (72 μL, 2.3 mmol, 3.0 equiv) in DCM (2.1 mL, 0.2M) were stirred at room temperature for 20 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.1 mL, 0.2 M). The suspension was treated with 1M HCl (0.84 mL, 31 mg, 0.84 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (147 μL, 109 mg, 0.84 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Normal phase chromatography (100% hexanes to 100% EtOAc) afforded 4l as a white solid (53.5 mg, 0.14 mmol 32%). R_f = 0.44 (5% MeOH in DCM); mp 194.2–195.6 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.18–3.24 (complex, 2H), 3.30–3.38 (complex, 2H), 5.91 (s, 2H), 6.81–6.89 (complex, 2H), 7.17 (dd, J = 1.6, 4.8 Hz, 1H), 7.31–7.39 (complex, 2H), 7.41–7.49 (complex, 2H), 7.65–7.69 (m, 1H), 7.75–7.85 (complex, 4H), 8.34 (dt, J = 1.1, 8.0 Hz, 1H), 8.63 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 27.5, 33.7, 43.4, 123.8, 124.2, 125.6, 126.2, 126.2, 126.6, 126.8, 126.8, 127.1, 127.7, 127.8, 128.4, 132.4, 133.8, 137.2, 138.3, 138.7, 148.3, 148.7, 151.6, 156.2. IR (neat) 3048, 1588 cm⁻¹. HRMS calcd for C₂₄H₂₁N₄S⁺ [M+H]⁺ 397.1481, found 397.1474. Purity (HPLC) >99%.

2-(5-( 1,2,3,4-Tetrahydronaphthalen-2-yl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (5a).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (39 mg, 0.17 mmol, 1.0 equiv), 1,2,3,4-tetrahydronaphthalene-2-carbohydrazide (9o) (38 mg, 0.20 mmol, 1.2 equiv), AgOBz (77 mg, 0.34 mmol, 2.0 equiv), and HOAc (29 μL, 30 mg, 0.50 mmol, 3.0 equiv) in DCM (0.8 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (0.8 mL). The suspension was treated with 1M HCl (0.34 mL, 13 mg, 0.34 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (29 μL, 22 mg, 0.34 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 5a as a white solid (20.3 mg, 0.054 mmol, 32%). R_f = 0.49 (5% MeOH in DCM); mp 125.7–130.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 2.05–2.25 (complex, 2H), 2.93–3.04 (complex, 3H), 3.23 (tt, J = 3.8, 11.7 Hz, 1H), 3.34–3.49 (m, 1H), 6.09 (ABq, Δν_AB = 25.4 Hz, J_AB = 15.7 Hz, 2H), 6.84–6.91 (complex, 2H), 7.05–7.22 (complex, 5H), 7.35 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.84 (td, J = 1.8, 7.8 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.66 (d, J = 4.0 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 28.9, 29.5, 32.0, 34.7, 43.4, 124.0, 124.2, 126.0, 126.2, 126.5, 126.8, 129.1, 129.2, 135.5, 135.6, 137.3, 139.0, 148.3, 148.7, 151.5, 157.5, 159.8. IR (solid) 1589, 1493 cm⁻¹. HRMS calcd for C₂₂H₂₁N₄S⁺ [M+H]⁺ 373.1500, found 373.1465. Purity (HPLC) >99%.

(E)-2-(4-(Furan-2-ylmethyl)-5-(4-methyl-3-(trifluoromethyl)styryl)-4H-1,2,4-triazol-3-yl)pyridine (5d).

(E)-N-(Furan-2-ylmethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)prop-2-enethioamide (8u) (47 mg, 0.14 mmol, 1.0 equiv), 1-methyl-1H-imidazole-2-carbohydrazide (24 mg, 0.17 mmol, 1.2 equiv), AgOBz (66 mg, 0.29 mmol, 2.0 equiv), and HOAc (25 μL, 26 mg, 0.44 mmol. 3.0 equiv) in DCM (0.6 mL, 0.2 M) were stirred at room temperature for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.29 mL, 38 mg, 0.29 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (52 μL, 38 mg, 0.29 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Normal phase chromatography (100% hexanes to 100% EtOAc) afforded 5d as a white oil (19.4 mg, 0.47 mmol, 33%). R_f = 0.27 (2.5:1.5 DCM:EA). ¹H NMR (500 MHz, chloroform-d) δ 2.51 (s, 3H), 6.11 (s, 2H), 6.28 (q, J = 2.5 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 7.15 (dd, J = 2.2, 16.2 Hz, 1H), 7.29–7.37 (complex, 2H), 7.39 (dd, J = 4.2, 8.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.79–7.89 (complex, 2H), 8.07 (d, J = 16.3 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.70 (dd, J = 2.5, 4.9 Hz, 1H); ¹³C NMR (126 MHz, chloroform-d) δ 19.4 (q, J = 2.3 Hz), 41.8, 109.6, 109.8, 110.8, 124.2, 124.4 (q, J = 274.4 Hz), 124.6, 124.7 (overlapping q with 124.6, J = 5.4 Hz), 129.6 (q, J = 30.06 Hz), 130.8, 132.7, 133.5, 137.4, 137.6, 138.0, 138.2, 143.2, 147.3, 148.7, 148.8, 151.2, 153.9; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.9. IR (neat) 1733, 1638 cm⁻¹. HRMS calcd for C₂₂H₁₈F₃N₄O⁺ [M+H]⁺ 411.1427, found 411.1432. Purity (HPLC) = 98%.

1-Phenyl-2-(5-(pyridin-2-yl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)ethan-1-ol (5h).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (150 mg, 0.64 mmol, 1.0 equiv), 3-hydroxy-3-phenylpropanehydrazide (9p) (138 mg, 0.77 mmol, 1.2 equiv), AgOBz (293 mg, 1.3 mmol, 2.0 equiv), and HOAc (110 μL, 115 mg, 1.9 mmol, 3.0 equiv) in DCM (3.0 mL, 0.2 M) were stirred at room temperature for 20 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (1.3 mL, 46 mg, 1.3 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (229 μL, 165 mg, 1.3 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Reverse phase chromatography (100% 0.1% formic acid in water to 100% acetonitrile) afforded 5h as a white solid (91.9 mg, 0.25 mmol, 40%). R_f = 0.34 (100% EtOAc); mp 207.3–214.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.13–3.31 (complex, 2H), 5.35 (dd, J = 4.0, 8.3 Hz, 1H), 5.98 (ABq, Δδ_AB = 0.28, J_AB = 15.7 Hz, 2H), 6.84–6.92 (complex, 2H), 7.19 (dd, J = 1.5, 4.8 Hz, 1H), 7.28–7.35 (m, 1H), 7.35–7.42 (complex, 3H), 7.42–7.49 (complex, 2H), 7.86 (td, J = 1.8, 7.8 Hz, 1H), 8.33 (dt, J = 1.1, 8.0 Hz, 1H), 8.67 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 35.3, 43.6, 71.4, 123.8, 124.5, 125.9, 126.5, 126.90, 126.93, 128.0, 128.8, 137.4, 138.0, 142.9, 147.7, 148.8, 151.4, 155.1. IR (solid) 3462, 1586 cm⁻¹. HRMS calcd for C₂₀H₁₉N₄OS⁺ [M+H]⁺ 363.1274, found 363.1266. Purity (HPLC) >99%.

2-(5-Phenyl-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (5j).

N-(Thiophen-2-ylmethyl)pyridine-2-carbothioamide (8b) (80 mg, 0.34 mmol, 1.0 equiv), benzohydrazide (56 mg, 0.41 mmol, 1.2 equiv), AgOBz (156 mg, 0.68 mmol, 2.0 equiv), and HOAc (58 μL, 61 mg, 1.0 mmol, 3.0 equiv) in DCM (1.6 mL, 0.2 M) were stirred at room temperature for 18 h. The reaction was concentrated, and the resulting oil was suspended in methanol (1.6 mL). The suspension was treated with 1M HCl (0.68 mL, 25 mg, 0.68 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (122 μL, 88 mg, 0.68 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 5j as a white solid (32.2 mg, 0.10 mmol, 30%). R_f = 0.39 (100% EtOAc); mp 161.9–169.2 °C. ¹H NMR (400 MHz, chloroform-d) δ 6.12 (s, 2H), 6.51 (dd, J = 1.1, 3.5 Hz, 1H), 6.77 (dd, J = 3.5, 5.1 Hz, 1H), 7.10 (dd, J = 1.2, 5.1 Hz, 1H), 7.40 (ddd, J = 1.2, 4.8, 7.7 Hz, 1H), 7.51–7.59 (complex, 3H), 7.58–7.69 (complex, 2H), 7.87 (td, J = 1.8, 7.8 Hz, 1H), 8.40 (dt, J = 1.1, 8.0 Hz, 1H), 8.69 (ddd, J = 1.0, 1.8, 4.8 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 44.4, 124.2, 124.6, 126.1, 126.6, 126.7, 126.7, 129.1, 129.8, 130.8, 137.4, 138.5, 147.7, 148.9, 152.0, 156.6. IR (solid) 1583, 1472 cm⁻¹. HRMS calcd for C₁₈H₁₅N₄S⁺ [M+H]⁺ 319.1012, found 319.1014. Purity (HPLC) >99%.

(E)-2-(5-(4-Methyl-3-(trifluoromethyl)styryl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (6a).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiophen-2-ylmethyl)prop-2-enethioamide (8v) (72 mg, 0.21 mmol, 1.0 equiv), picolinohydrazide (35 mg, 0.25 mmol, 1.2 equiv), AgOBz (96 mg, 0.41 mmol, 2.0 equiv), and HOAc (36 μL, 38 mg, 0.63 mmol, 3.0 equiv) in DCM (0.6 mL, 0.4 M) were stirred at room temperature for 16.5 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.42 mL, 15 mg, 0.42 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (75 μL, 54 mg, 0.42 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) followed by reverse phase chromatography (100% water to 100% MeOH) afforded 6a as a white solid (23.9 mg, 0.056 mmol, 27%). R_f = 0.53 (100% EtOAc); mp 138.0–146.4 °C. ¹H NMR (600 MHz, chloroform-d) δ 2.51 (s, 3H), 6.19 (s, 2H), 6.92 (dd, J = 3.5, 5.1 Hz, 1H), 6.97–7.03 (complex, 2H), 7.21 (dd, J = 1.3, 5.1 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.36 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.58 (dd, J = 1.9, 8.0 Hz, 1H), 7.77 (s, 1H), 7.84 (td, J = 1.8, 7.8 Hz, 1H), 7.87 (d, J = 16.0 Hz, 1H), 8.38 (dt, J = 1.1, 8.0 Hz, 1H), 8.68 (ddd, J = 0.9, 1.7, 4.8 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.4 (d, J = 1.9 Hz), 43.4, 111.2, 123.9, 124.3, 124.4 (q, J = 228.6 Hz), 124.4 (q, J = 4.6 Hz), 126.3, 126.8, 127.0, 129.7 (q, J = 25.1 Hz), 130.4, 132.7, 133.8, 135.8, 137.2, 137.7, 138.5, 148.0, 148.7, 151.6, 154.2; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.9. IR (neat) 1732, 1590 cm⁻¹. HRMS calcd for C₂₂H₁₈F₃N₄S⁺ [M+H]⁺ 427.1199, found 427.1203. Purity (HPLC) >99%.

(E)-2-((3-(4-Methyl-3-(trifluoromethyl)styryl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-yl)methyl)thiazole (6b).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiazol-2-ylmethyl)prop-2-enethioamide (8w) (45 mg, 0.13 mmol, 1.0 equiv), picolinohydrazide (22 mg, 0.16 mmol, 1.2 equiv), AgOBz (60 mg, 0.26 mmol, 2.0 equiv), and HOAc (23 μL, 24 mg, 0.40 mmol, 3 equiv) in DCM (0.3 mL, 0.4 M) were reacted at room temperature for 20 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.26 mL, 9.6 mg, 0.26 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (47 μL, 34 mg, 0.26 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) followed by reverse phase chromatography (100% 0.1% formic acid in water to 100% methanol) afforded 6b as a clear, colorless oil (5.5 mg, 0.013 mmol, 10%). R_f = 0.42 (100% EtOAc). ¹H NMR (500 MHz, chloroform-d) δ 2.51 (d, J = 1.8 Hz, 3H), 6.28 (s, 2H), 7.28–7.35 (complex, 3H), 7.39 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.65 (dd, J = 1.9, 7.8 Hz, 1H), 7.80 (d, J = 3.2 Hz, 1H), 7.81 (s, 1H), 7.87 (dd, J = 1.8, 7.8 Hz, 1H), 7.9 (d, J = 16.0 Hz, 1H), 8.43 (dt, J = 1.1, 8.1 Hz, 1H), 8.70 (d, J = 8.70 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.4 (d, J = 2.2 Hz), 46.0, 111.4, 121.3, 123.8, 124.4, 124.4 (q, J = 274.0 Hz), 124.9 (q, J = 5.6 Hz), 129.6 (q, J = 29.9 Hz), 130.3, 132.6, 133.9, 136.2, 137.5, 137.8, 142.7, 147.7, 148.7, 151.4, 154.8, 164.3; ¹⁹F NMR (471 MHz, chloroform-d) δ −61.9. IR(neat) 1589, 1503 cm⁻¹. HRMS calcd for C₂₁H₁₇F₃N₅S⁺ [M+H]⁺ 428.1151, found 428.1154. Purity (HPLC) = 97%.

(E)-4-(Furan-2-ylmethyl)-3-(1-methyl-1H-imidazol-2-yl)-5-(4-methyl-3-(trifluoromethyl)styryl)-4H-1,2,4-triazole (6c).

(E)-N-(Furan-2-ylmethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)prop-2-enethioamide (8u) (41 mg, 0.13 mmol, 1.0 equiv), 1-methyl-1H-imidazole-2-carbohydrazide (21 mg, 0.15 mmol, 1.2 equiv), AgOBz (58 mg, 0.25 mmol, 2.0 equiv), and HOAc (22 μL, 22.8 mg, 3.0 equiv) in DCE (0.6 mL, 0.2 M) were stirred at 60 °C for 1.5 days. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.25 mL, 9.2 mg, 0.25 mmol, 2.0 equiv) to form a black solid. The reaction was then treated with DIPEA (45 μL, 33 mg, 0.25 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) followed by reverse phase chromatography (100% water to 100% methanol) afforded 6c as a white oil (5.8 mg, 0.014 mmol, 11%). R_f = 0.42 (100% EtOAc). ¹H NMR (400 MHz, chloroform-d) δ 2.52 (d, J = 1.9 Hz, 3H), 4.10 (s, 3H), 5.97 (s, 2H), 6.28 (dd, J = 1.9, 3.3 Hz, 1H), 6.33 (d, J = 3.3 Hz, 1H), 7.04 (d, J = 1.1 Hz, 1H), 7.11 (d, J = 16.0 Hz, 1H), 7.20 (d, J = 1.2 Hz, 1H), 7.29–736 (complex, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 16.1 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.4 (q, J = 2.0 Hz), 36.1, 41.1, 109.6, 110.8, 111.3, 124.0, 124.4 (q, J = 274.0 Hz), 124.5 (q, J = 5.67 Hz), 128.8, 129.7 (q, J = 29.9 Hz), 130.4, 132.7, 133.9, 135.6, 136.0, 137.7, 143.0, 145.9, 149.1, 153.1; ¹⁹F NMR (376 MHz, chloroform-d) δ −61.9. IR (neat) 1508, 1446 cm⁻¹. HRMS calcd for C₂₁H₁₉F₃N₅O⁺ [M+H]⁺ 414.1536, found 414.1541. Purity (HPLC) >99%.

(E)-3-(1-Methyl-1H-imidazol-2-yl)-5-(4-methyl-3-(trifluoromethyl)styryl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazole (6d).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiophen-2-ylmethyl)prop-2-enethioamide (8v) (32 mg, 0.092 mmol, 1.0 equiv), 1-methyl-1H-imidazole-2-carbohydrazide (16 mg, 0.11, 1.2 equiv), AgOBz (42 mg, 0.19 mmol, 2.0 equiv), and HOAc (16 μL, 17 mg, 0.28 mmol, 3.0 equiv) in DCE (0.45 mL, 0.2 M) were stirred at 60°C for 2.5 days. The reaction was concentrated, and the resulting oil was suspended in methanol (1.0 mL). The suspension was treated with 1M HCl (0.19 mL, 6.7 mg, 0.19 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (33 μL, 24 mg, 0.19 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% DCM to 100% EtOAc) afforded 6d as a white solid (5.8 mg, 0.014 mmol, 6%). R_f = 0.22 (1:1 DCM:EtOAc); mp 145.8–151.1 °C. ¹H NMR (500 MHz, chloroform-d δ 2.51 (d, J = 2.0 Hz, 3H), 4.08 (s, 3H), 6.16 (s, 2H), 6.91 (dd, J = 3.5, 5.1 Hz, 1H), 6.94–7.04 (complex, 2H), 7.08 (d, J = 1.2 Hz, 1H), 7.20 (dd, J = 1.2, 5.1 Hz, 1H), 7.24 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.93 (d, J = 16.0 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d δ 19.4 (q, J = 2.26 Hz), 36.1, 43.2, 110.4, 124.2, 124.4 (q, J = 274.1 Hz), 124.6 (q, J = 5.6 Hz), 126.4, 127.20, 127.22, 128.4, 129.7 (q, J = 30.0 Hz), 130.5, 132.7, 133.6, 135.4, 136.8, 137.8, 138.1, 145.3, 152.8; ¹⁹F NMR (471 MHz, chloroform-d) δ −62.0. IR(solid) 1643, 1506 cm−1. HRMS calcd for C₂₁H₁₉F₃N₅S⁺ [M+H]⁺ 430.1308 found, 430.1302. Purity (HPLC) = 97%.

(E)-2-((3-(1-Methyl-1H-imidazol-2-yl)-5-(4-methyl-3-(trifluoromethyl)styryl)-4H-1,2,4-triazol-4-yl)methyl)thiazole (6e).

(E)-3-(4-Methyl-3-(trifluoromethyl)phenyl)-N-(thiazol-2-ylmethyl)prop-2-enethioamide (8w) (60 mg, 0.18 mmol, 1.0 equiv), 1-methyl-1H-imidazole-2-carbohydrazide (29 mg, 0.21 mmol, 1.2 equiv), AgOBz (80 mg, 0.25 mmol, 2.0 equiv), and HOAc (30 μL, 32 mg, 0.53 mmol, 3.0 equiv) in DCE (0.9 mL 0.2 M) were stirred at 60 °C for 17 h. The reaction was concentrated, and the resulting oil was suspended in methanol (2.0 mL). The suspension was treated with 1M HCl (0.35 mL, 13 mg, 0.35 mmol, 2.0, equiv) to form a black solid. The reaction was then treated with DIPEA (63 μL, 45 mg, 0.35 mmol, 2.0 equiv). The reaction mixture was filtered over Celite, eluted with methanol, and concentrated. The residue was diluted with EtOAc and washed twice with 1M potassium bisulfate and twice with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Flash chromatography (100% hexanes to 100% EtOAc) followed by preparative TLC (75% EtOAc in hexanes) afforded 6e as a white solid (6.2 mg, 0.014 mmol, 8%). R_f = 0.48 (5% MeOH in DCM); mp 146.3–152.0 °C. ¹H NMR (500 MHz, chloroform-d δ 2.48 (d, J = 2.1 Hz, 3H), 4.14 (s, 3H), 6.27 (s, 2H), 7.05 (d, J = 1.1 Hz, 1H), 7.19 (d, J = 1.1 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 7.30 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.76 (s, 1H), 7.82 (d, J = 16.2 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 19.4 (q, J = 2.2 Hz), 36.2, 45.6, 111.4, 121.3, 124.2, 124.4 (q, J = 124.0 Hz), 124.9 (q, J = 5.6 Hz), 128.9, 129.6 (q, J = 30.0 Hz), 130.2, 132.6, 133.9, 135.8, 135.9, 137.7, 142.7, 145.8, 153.4, 164.0; ¹⁹F NMR (471 MHz, chloroform-d) δ −61.9. IR (neat) 1508, 1444 cm⁻¹. HRMS calcd for C₂₀H₁₈F₃N₆S⁺ [M+H]⁺ 431.1260, found 431.1265. Purity (HPLC) = 95%.

Synthesis of intermediates 12-17

Compounds 12 and 13 were synthesized as described in the literature. Characterization is consistent with that reported.[38]

(2-(4-(Furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (14).

4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (13) (182 mg, 0.71 mmol, 1.0 equiv) was slurried in DCM (1.4 mL, 0.5 M) and cooled to 0 °C. A solution of H₂O₂ (159 μL, 176 mg, 30% Wt, 1.5 mmol, 2.2 equiv) and HOAc (1.0 mL, 0.67 M) was added dropwise to the DCM solution. The reaction stirred at 0 °C for 10 minutes then was removed from the ice bath and warmed to room temperature. After 5.5 hours, the reaction was alkalized using 6M NaOH to pH12. The solution was washed twice with DCM and the combined organic layers were dried with sodium sulfate and purified via flash chromatography (100% DCM to 0.8% MeOH, in DCM) to afford 14 as a brown solid (82.6 mg, 0.36 mmol, 52%). R_f = 0.39 (5% MeOH, in DCM); mp 118.7–128.1 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.94 (s, 2H), 6.32 (dd, J = 1.9, 3.3 Hz, 1H), 6.37 (dq, J = 0.7, 3.3 Hz, 1H), 7.37–7.42 (complex, 2H), 7.86 (td, J = 1.8, 7.8 Hz, 1H), 8.37 (dt, J = 1.1, 8.0 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.69 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 43.1, 109.8, 110.8, 123.7, 124.3, 137.2, 143.4, 145.6, 148.0, 148.7, 148.7, 151.0. IR (solid) 3108, 1589, 1522, 1503, 1447 cm⁻¹. HRMS calcd for C₁₂H₁₁N₄O⁺ [M+H]⁺ 227.0927, found 227.0918. Purity (HPLC) = 92%.

(4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)methanol (15).

2-(4-(Furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (14) (812 mg, 3.6 mmol, 1.0 equiv) was slurried in p-xylene (18 mL, 0.2 M). Formaldehyde (529 mg, 18.0 mmol, 5.0 equiv) was added and the reaction was heated to 125 °C for 4 h. The reaction was heated over celite and purified via flash chromatography (100% DCM to 0.8% MeOH, in DCM) to afford 15 as a white solid (279.3 mg, 1.1 mmol, 30%). R_f = 0.30 (5% MeOH, in DCM); mp 136.5–143.5 °C. ¹H NMR (400 MHz, chloroform-d) δ 5.02 (s, 2H), 6.06 (s, 2H), 6.22 (t, J = 1.2 Hz, 2H), 7.28 (dd, J = 1.0, 1.7 Hz, 1H), 7.35 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.81 (td, J = 1.8, 7.8 Hz, 1H), 8.25 (dt, J = 1.1, 8.0 Hz, 1H), 8.67 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 41.5, 55.1, 109.1, 110.5, 123.8, 124.3, 137.1, 142.9, 147.9, 148.7, 149.4, 152.3, 156.3. IR (solid) 3141, 2840 cm⁻¹. HRMS calcd for C₁₃H₁₃N₄O⁺ [M+H]⁺ 257.1033, found 257.1031. Purity (HPLC) >99%.

4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (16).

(4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)methanol (15) (440 mg, 1.7 mmol, 1.0 equiv) and manganese(IV) oxide (1.57 g, 18.0 mmol, 10.5 equiv) were slurried in THF (7.8 mL, 0.2 M). After stirring for 4 h at room temperature, the reaction was filtered over Celite and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 16 as a white solid (289.1 mg, 1.1 mmol, 66%). R_f = 0.59 (100% EtOAc); mp 144.7–148.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 6.16–6.24 (m, 2H), 6.43 (s, 2H), 7.19 (dd, J = 0.8, 1.8 Hz, 1H), 7.44 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.89 (td, J = 1.8, 7.8 Hz, 1H), 8.37 (dt, J = 1.1, 8.0 Hz, 1H), 8.74 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H), 10.20 (s, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 42.2, 109.4, 110.4, 125.1, 125.2, 137.4, 143.1, 147.1, 149.1, 151.9, 154.1, 182.2. IR (solid) 1693, 1586 cm⁻¹. HRMS calcd for C₁₃H₁₁N₄O₂⁺ [M+H]⁺ 255.0877, found 255.0871. Purity (HPLC) = 87%.

2-(5-Ethynyl-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (17).

4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (16) (238 mg, 934 mmol, 1.0 equiv) and dimethyl (1-diazo-2-oxopropyl)phosphonate (182 μL, 233 mg, 1.2 mmol, 2.0 equiv) were dissolved in MeOH (934 μL, 0.2 M) under anhydrous conditions. Potassium carbonate (260 mg, 1.9 mmol, 2.0 equiv) was added and the reaction stirred at room temperature for 18 h. The reaction was quenched with saturated ammonium chloride and extracted 3 times with ethyl acetate. The combined organic layers were washed with water and brine and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 17 as a white solid (124.2 mg, 0.50 mmol, 53%). R_f = 0.62 (100% EtOAc); mp 155.4–159.8 °C. ¹H NMR (400 MHz, chloroform-d) δ 3.65 (s, 1H), 6.02 (s, 2H), 6.18 (dq, J = 0.8, 3.4 Hz, 1H), 6.21 (dd, J = 1.8, 3.3 Hz, 1H), 7.37 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.32 (dt, J = 1.1, 8.0 Hz, 1H), 8.68 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 42.6, 70.0, 86.7, 109.3, 110.5, 124.1, 124.6, 137.2, 141.9, 142.9, 147.5, 148.8, 149.0, 151.3. IR (solid) 3170, 2123 cm⁻¹. HRMS calcd for C₁₄H₁₁N₄O⁺ [M+H]⁺ 251.0927, found 251.0923. Purity (HPLC) >99%.

Synthesis of triazoles 5b, 5c, 5e, 5f, 5g, 5i

2-(4-(Furan-2-ylmethyl)-5-(phenylethynyl)-4H-1,2,4-triazol-3-yl)pyridine (5b).

Iodobenzene (16 mg, 0.78 mmol, 1.0 equiv), 2-(5-ethynyl-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (17) (39 mg, 0.16 mmol, 2.0 equiv), CuI (1.8 mg, 0.0093 mmol, 0.12 equiv), and PdCl₂(PPh₃)₂ (3.3 mg, 0.0047 mmol, 0.060 equiv.) were reacted in degassed TEA (435 μL, 315 mg, 3.1 mmol, 0.2M) for 18.5 h at 75°C. The solvent was evaporated. The residue was partitioned in EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic layers were dried with sodium sulfate, concentrated, and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 5b as a white solid (9.6 mg, 0.029 mmol, 38%). R_f = 0.42 (50% EtOAc in hexanes); mp 165.5–169.7°C. ¹H NMR (400 MHz, chloroform-d) δ 6.07 (s, 2H), 6.19–6.25 (complex, 2H), 7.27 (dd, J = 1.0, 1.7 Hz, 1H), 7.32–7.48 (complex, 4H), 7.59–7.66 (complex, 2H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.35 (dt, J = 1.1, 8.1 Hz, 1H), 8.68 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 42.6, 75.3, 98.2, 109.3, 110.6, 121.2, 124.0, 124.5, 128.8, 130.1, 132.2, 137.2, 142.9, 143.0, 147.6, 148.8, 149.3, 151.2. IR (solid) 2223, 1587. HRMS cald for C₂₀H₁₅N₄O⁺ [M+H]⁺ 327.1240, found 327.1238. Purity (HPLC) >99%.

(Z)-2-(4-(Furan-2-ylmethyl)-5-styryl-4H-1,2,4-triazol-3-yl)pyridine (5c).

To 2-(4-(furan-2-ylmethyl)-5-(phenylethynyl)-4H-1,2,4-triazol-3-yl)pyridine (5b) (17 mg, 0.051 mmol, 1.0 equiv) dissolved in THF (0.26 mL, 0.2 M) was added Lindlar’s catalyst (1.0 mg, 0.010 mmol, 0.02 equiv). The suspension was sparged with H₂ for 4 minutes. The reaction stirred under H₂ for 3 hours. The suspension was then filtered over celite and concentrated. Flash chromatography (100% Hex to 100% EtOAc) afforded 5c as a clear, colorless oil (5.7 mg, 0.017 mmol, 34%). R_f = 0.49 (100% EtOAc). ¹H NMR (400 MHz, Chloroform-d) δ 5.76 (s, 2H), 6.09 (dd, J = 0.8, 3.3 Hz, 1H), 6.18 (dd, J = 1.8, 3.3 Hz, 1H), 6.52 (d, J = 12.5 Hz, 1H), 7.07 (d, J = 12.5 Hz, 1H), 7.22 (dd, J = 0.9, 1.9 Hz, 1H), 7.26–7.30 (complex, 3H), 7.33 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.46–7.54 (m, 2H), 7.82 (td, J = 1.8, 7.8 Hz, 1H), 8.35 (dt, J = 1.1, 8.0 Hz, 1H), 8.64 (d, J = 4.5 Hz, 1H); ¹³C NMR (101 MHz, cdcl₃) δ 41.6, 108.7, 110.3, 112.8, 123.7, 124.0, 128.4, 128.9, 129.3, 135.1, 137.0, 139.3, 142.5, 147.9, 148.5, 149.3, 151.3, 153.3. HMRS calcd for C₂₀H₁₇N₄O⁺ [M+H]⁺ 329.1397, found 329.1388. Purity (HPLC) = 90%.

1-(4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-phenylethan-1-ol (5e).

4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazole-3-carbaldehyde (16) (125 mg, 0.49 mmol, 1.0 equiv) was dissolved in THF (2.0 mL, 0.25 M) under dry, anhydrous conditions. Benzylmagnesium chloride (246 μL, 74 mg, 2 molar, 1.0 equiv) was added dropwise to the solution which stirred at room temperature for 1 h. The reaction was poured onto water and extracted three times with EtOAc. The combined organic layers were dried with sodium sulfate, concentrated, and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 5e as a yellow oil (116.7 mg, 0.34 mmol, 68%). R_f = 0.37 (100% EtOAc). ¹H NMR (400 MHz, chloroform-d) δ 3.42 (AB of ABX, J_AB = 13.9 Hz, J_AX = 5.5 Hz, J_BX = 8.3 Hz, 2H), 5.36 (X of ABX, J_AB = 13.9 Hz, J_AX = 5.5 Hz, J_BX = 8.3 Hz, 1H), 5.91 (ABq, Δδ_AB = 0.14, J_AB = 15.8 Hz, 2H), 6.04–6.10 (m, 1H), 6.19 (dd, J = 1.9, 3.3 Hz, 1H), 7.21–737 (complex, 7H), 7.80 (td, J = 1.8, 7.8, Hz, 1H), 8.24 (dt, J = 1.1, 8.0 Hz, 1H), 8.63 (ddd, J = 0.9, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 41.4, 42.2, 67.0, 108.9, 110.6, 124.0, 124.3, 127.0, 128.8, 129.8, 137.2, 137.2, 142.7, 148.0, 148.6, 149.5, 152.3, 157.5. IR (neat) 3200, 1589 cm⁻¹. HRMS cald for C₂₀H₁₉N₄O₂⁺ [M+H]⁺ 347.1502, found 347.1491. Purity (HPLC) = 94%.

1-(4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-phenylethan-1-one (5f).

1-(4-(Furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-phenylethan-1-ol (5e) (119 mg, 0.34 mmol, 1.0 equiv) and MnO₂ (315 mg, 3.6 mmol, 10 equiv) was dissolved in anhydrous THF (1.6 mL, 0.22 molar) under argon. The reaction stirred at room temperature for 24 h. The resulting mixture was filtered over Celite and purified via flash chromatography (100% hexanes to 100% EtOAc) to afford 5f as a yellow oil (19.6 mg, 0.057 mmol, 16%). R_f = 0.67 (75% EtOAc in hexanes). ¹H NMR (400 MHz, chloroform-d) δ 2.47 (s, 2H), 6.15–6.22 (complex, 2H), 6.53 (s, 2H), 7.18 (dd, J = 0.9, 1.8 Hz, 1H), 7.27–7.32 (complex, 2H), 7.39–7.49 (complex, 2H), 7.72 (dd, J = 1.4, 7.7 Hz, 1H), 7.88 (td, J = 1.8, 7.8 Hz, 1H), 8.36 (dt, J = 1.1, 8.0 Hz, 1H), 8.75 (ddd, J = 0.9, 1.8, 4.8 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 20.7, 42.3, 109.1, 110.5, 124.9, 125.1, 125.5, 131.6, 131.7, 132.3, 136.7, 137.4, 139.1, 142.9, 147.5, 149.1, 149.8, 152.6, 153.6, 187.6. IR (neat) 1663, 1588 cm⁻¹. HRMS cald for C₂₀H₁₇N₄O₂⁺ 345.1346, found 345.1336. Purity (HPLC) >99%.

2-(5-(1-Fluoro-2-phenylethyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (5g).

An oven dried vial containing 1-(4-(furan-2-ylmethyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-phenylethan-1-ol (5e) (23 mg, 0.066 mmol, 1.0 equiv) was purged with argon and charged with anhydrous DCM (1.2 mL, 0.06 mM). The sealed vial was cooled to −78°C and DAST (21 mg, 17 μL, 0.066 mmol, 2.0 equiv) was added. The reaction stirred at −78°C and was slowly warmed to room temperature overnight. The reaction was then cooled to 0°C and quenched with 2 mL saturated sodium bicarbonate. The aqueous layer was extracted three times with DCM. Flash chromatography (100% hexanes to 100% EtOAc) afforded 5g as a clear, colorless oil (13.0 mg, 0.037 mmol, 57%). R_f = 0.61 (100% EtOAc). ¹H NMR (400 MHz, chloroform-d) δ 3.60–3.81 (complex, 2H), 6.00 (ABq, Δδ_AB = 0.76, J_AB = 17.8 Hz, 2H), 6.02 (ddd, J = 5.2, 8.2, 49.2 Hz, 1H), 6.12 (dd, J = 0.8, 3.3 Hz, 1H), 6.20 (dd, J = 1.9, 3.3 Hz, 1H), 7.24–7.41 (complex, 7H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.31 (dt, J = 1.1, 8.0 Hz, 1H), 8.67 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (101 MHz, chloroform-d) δ 38.8 (d, J = 21.8 Hz), 41.6 (d, J = 4.0 Hz), 86.0 (d, J = 171.3 Hz), 109.1, 110.6, 124.2, 124.5, 127.2, 128.7, 129.8, 136.2 (d, J = 3.4 Hz), 137.2, 142.9, 147.9, 148.7, 149.1, 152.9, 153.6 (d, J = 21.7 Hz); ¹⁹F NMR (376 MHz, chloroform-d) δ −176.79 (ddd, J = 18.5, 29.2, 53.3 Hz). IR (neat) 3028, 1589 cm⁻¹. HRMS calcd for C₂₀H₁₈FN₄O⁺ [M+H]⁺ 349.1459, found 349.1452. Purity (HPLC) >99%.

2-(5-(2-Fluoro-2-phenylethyl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)pyridine (5i).

An oven dried vial containing 1-phenyl-2-(5-(pyridin-2-yl)-4-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)ethan-1-ol (5h) (28 mg, 0.076 mmol, 1.0 equiv) was purged with argon and charged with anhydrous DCM (4.2 mL, 18 mM). The sealed vial was cooled to −78°C and DAST (24.1 mg, 20 μL, 149 mmol, 2.0 equiv) was added dropwise. The reaction stirred at −78°C and was slowly warmed to room temperature overnight. The reaction was then cooled to 0°C and quenched with 5 mL saturated sodium bicarbonate. The aqueous layer was extracted three times with DCM. Flash chromatography (100% hexanes to 100% EtOAc) afforded 5i as a clear, colorless oil (19.9 mg, 0.055 mmol, 72%). R_f = 0.37 (100% EtOAc). ¹H NMR (400 MHz, chloroform-d) δ 3.33–3.59 (m, 2H), 6.02 (ddd, J = 4.5, 8.5, 46.9 Hz, 1H), 6.01 (ABq, Δδ_AB = 0.34, J_AB = 15.7 Hz, 2H), 6.86–6.91 (complex, 2H), 7.18 (dd, J = 2.0, 4.4 Hz, 1H), 7.33–7.39 (complex, 2H), 7.41 (dt, J = 0.9, 4.3 Hz, 4H), 7.83 (td, J = 1.8, 7.8 Hz, 1H), 8.33 (dt, J = 1.1, 8.0 Hz, 1H), 8.65 (ddd, J = 1.0, 1.8, 4.9 Hz, 1H); ¹³C NMR (151 MHz, chloroform-d) δ 36.4 (d, J = 26.5 Hz), 46.0 (d, J = 3.2 Hz), 95.6 (d, J = 174.3 Hz), 126.4, 126.8, 128.2 (d, J = 7.0 Hz), 128.8, 129.1, 129.4, 131.5, 131.6 (d, J = 2.0 Hz), 139.8, 141.1, 141.4 (d, J = 19.8 Hz), 150.6, 151.3, 154.3, 155.64 (d, J = 4.4 Hz); ¹⁹F NMR (376 MHz, chloroform-d) δ −173.2 (ddd, J = 13.6, 29.7, 47.0 Hz). IR (solid) 3076, 1587 cm⁻¹. HRMS calcd for C₂₀H₁₈FN₄S⁺ [M+H]⁺ 365.1231, found 365.1226. Purity (HPLC) = 96%.

4.3. Docking Studies

Ligands were docked with AutoDock Vina[59] into an electron microscopy KOR structure, captures in the active state at 2.71 Å resolution (PDB 8DZP).[50] The AutoDock Vina tool in Chimera[60] was used to select the orthosteric binding site as the search volume, with energy range set to 3 kcal/mol and exhaustiveness value to 8. Output files describing the receptor, ligand, and configuration were imported into the separate AutoDock Vina program and used to generate the ten docking positions predicted to be most energetically favorable within the selected search volume. The pose with the lowest docking score and at least one predicted hydrogen bond with the receptor was selected as the final docking position. Images were generated and distances to nearby residues were measured using Chimera.

4.4. Biology

4.4.1. Compounds and reagents

Reference compound U69,593 was purchased from Sigma Aldrich and prepared in DMSO as a 10 mM stock solution. Test compounds were prepared as 10 mM stock solutions in DMSO. All compounds were then diluted to working concentrations in vehicle for each assay without exceeding 1% DMSO concentrations.

4.4.2. Cell lines and cell culture

Chinese hamster ovary (CHO) cells expressing recombinant human kappa opioid receptor (CHO-hKOR cell line) were maintained in DMEM/F-12 media (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin, and 500 μg/ml geneticin. The DiscoveRx PathHunter^™ U2OS cell line expressing βarrestin2 and hKOR (U2OS-hK0R-βarrestin2-DX) were purchased from Eurofins DiscoverX Products (Fremont, CA) and maintained MEM with 10% fetal bovine serum, 1% penicillin/streptomycin, 500 μg/ml geneticin, and 250 μg/ml hygromycin B. All cells were grown at 37 °C (5% CO₂ and 95% relative humidity).

4.4.3. Signaling assays

³⁵S-GTPγS binding assays were performed on membranes prepared from the CHO-hKOR cells as previously described.[39, 61] For each reaction, 15 mg of membrane protein was incubated in an assay buffer (50 mM Tris, 100 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, pH 7.4 (all compounds from Fisher Scientific, USA) with 3 μM GDP (Millipore Sigma, USA) added prior to use) containing 0.1 nM [³⁵S]GTPγS (Revvity, USA) and compounds of increasing concentrations in a total volume of 200 mL for 1 hour at room temperature. The reactions were then filtrated through 96-well GF/B filter pads (Cytiva /Whatman/GE, Millipore Sigma, USA) or filter plates (PerkinElmer, USA) using a 96-well plate harvester (Brandel Inc., USA). The filters were dried at room temperature overnight, and the radioactivity was determined after addition of liquid scintillation fluid (Microscint^™-20, Revvity, USA) by a TopCount NXT Microplate Scintillation and Luminescence Counter (PerkinElmer Life Sciences).

The βarrestin2 recruitment (DiscoverX PathHunter^™) assay was performed in hKOR-expressing U2OS cells provided by the company according to the manufacturer’s protocol and following previously published protocols.[39]

4.4.4. Data analysis

Concentration–response curves were analyzed with GraphPad Prism 10 software (GraphPad) using a three-parameter, nonlinear regression analysis with data normalized to vehicle and maximal U96,593 stimulation. All compounds were run in parallel assays (2–4 replicates per individual experiment). All studies were performed n ≥ 3 independent experiments in multiple replicates. The efficacy and potency values were obtained from the replicate experiments and are presented with 95% confidence intervals. Bias analysis was carried out according by fitting to the operational model as we have described in detail.[39, 62] Δlog(τ/K_A) or “ΔlogR“ (logR_test-logR_U69) was calculated for each individual experiment and averaged to generate the mean ΔlogR for each test compound in each assay. The bias factor is derived from the subtraction of ΔlogR_{GTPγS binding} – ΔlogR_{βarr2 recruitment} to generate the ΔΔlogR_(GTP/βarr2) which reflects a preference for G protein signaling over βarrestin2 recruitment. The specific calculation of “bias,” or bias factor, is presented as the antilog of this difference in the normalized transduction coefficient (ΔΔlogR_(GTP/βarr2)).[39] In cases where the efficacy of the test compounded exceeded U69,593, we imposed constraints to the model: logK_A must fall between 0 and −15 and the ΔlogR must be a value less than 10.

4.4.5. Opioid receptor selectivity

Radioligand binding data were obtained by the UNC Psychoactive Drug Screening Program as previously reported.[63] Briefly, the ability of a 10 μM solution of the compound to inhibit binding of an appropriate labeled ligand was measured ([³H]-D-Ala², D-Leu⁵]-enkephalin) for DOR (at 0.88 nM), ([³H]-U69,693 for KOR (at 0.83 nM), or ([³H]-D-Ala², N-MePhe⁴, Gly-ol]-enkephalin for MOR (at 1.91 nM). The experiments were run in quadruplicate.

4.4.6. Microsomal stability

Hepatic microsomes (human or mouse, 1 mg/mL) were incubated with 1 μM test compound at 37°C, shaking continuously. Activity was quenched and proteins precipitated at 5 minute intervals over 1 hour using acetonitrile; samples were filtered through 0.45 μM filter plates. Samples were subjected to LC-MS/MS analysis to determine half life.[52]

Table 5.

Effect of C-5 Linker Substitution on KOR Agonist Activity

^a35S-GTPγS binding assay of KOR G protein activation (n ≥ 3).

^bβarrestin2 recruitment assay (n ≥ 3; for 5e, n=2).

^cBias factor as calculated by published methods.[39] EC₅₀ and E_max are presented with 95% confidence intervals. nc is nonconvergent to analysis.

• The kappa opioid receptor (KOR) is a target for the treatment of pain and itch

• Most KOR agonists cause dysphoria, a problematic side effect

• Biased KOR agonist selective for G-protein activation reduce dysphoria

• We report carbon-substituted triazoles as biased KOR agonists and examine their SAR

• A binding mode of this class to the KOR is proposed

ABBREVIATIONS

KOR

kappa opioid receptor

CI

confidence interval

CDI

1,1′-carbonyldiimidazole

MeOH

methanol

HOAc

acetic acid

ACN

acetonitrile

TEA

triethylamine

DAST

diethylaminosulfur trifluoride

TLC

thin-layer chromatography

MPLC

medium pressure liquid chromatography

UPLC

ultrahigh-performance liquid chromatography

DIPEA

N,N-diisopropylethylamine